Rebamipide protects against glaucoma eyedrop-induced ocular surface disorders in rabbits

PubMed Central

Kawaguchi, Ichiro; Higashide, Tomomi; Takeji, Yasuhiro; Sakurai, Kazushi; Kawaguchi, Chiaki; Sugiyama, Kazuhisa

2017-01-01

Purpose This study aimed to determine if rebamipide eyedrops can improve ocular surface damage caused by the use of glaucoma eyedrops. Methods Female Kbl:Dutch rabbits were used to evaluate glaucoma eyedrop-induced ocular surface damage; one eye of each rabbit was untreated and the other was administered glaucoma eyedrops for 30 days. To evaluate the effects of rebamipide on ocular surface damage, one eye of each rabbit was administered vehicle-treated glaucoma eyedrops and the other was administered rebamipide-treated glaucoma eyedrops for 30 days. Corneal and conjunctival epithelial damage was evaluated using fluorescein and rose bengal staining, respectively. Conjunctival inflammation was observed by light microscopy with hematoxylin-eosin staining. Dark cells (in which the corneal microvilli were damaged) were analyzed by scanning electron microscopy. Results There were no significant differences in fluorescein staining between the untreated and glaucoma eyedrop-treated groups; however, rose bengal staining and the number of inflammatory cells in the conjunctiva significantly increased after glaucoma eyedrop treatment. There was a four-fold increase in the number of dark cells in the glaucoma eyedrop-treated group compared to untreated. In contrast, in the conjunctiva of the rebamipide-treated glaucoma eyedrop group, rose bengal staining scores, the number of inflammatory cells, and the number of dark cells were decreased compared to the vehicle-treated glaucoma eyedrop group. Conclusions Results from our in vivo rabbit study demonstrated that short-term use of glaucoma eyedrops induces corneal epithelium disorders at the cellular level, but that simultaneous use of rebamipide has the potential to protect and repair the ocular surface. PMID:29049370

Rebamipide protects against glaucoma eyedrop-induced ocular surface disorders in rabbits.

PubMed

Kawaguchi, Ichiro; Kobayashi, Akira; Higashide, Tomomi; Takeji, Yasuhiro; Sakurai, Kazushi; Kawaguchi, Chiaki; Sugiyama, Kazuhisa

2017-01-01

This study aimed to determine if rebamipide eyedrops can improve ocular surface damage caused by the use of glaucoma eyedrops. Female Kbl:Dutch rabbits were used to evaluate glaucoma eyedrop-induced ocular surface damage; one eye of each rabbit was untreated and the other was administered glaucoma eyedrops for 30 days. To evaluate the effects of rebamipide on ocular surface damage, one eye of each rabbit was administered vehicle-treated glaucoma eyedrops and the other was administered rebamipide-treated glaucoma eyedrops for 30 days. Corneal and conjunctival epithelial damage was evaluated using fluorescein and rose bengal staining, respectively. Conjunctival inflammation was observed by light microscopy with hematoxylin-eosin staining. Dark cells (in which the corneal microvilli were damaged) were analyzed by scanning electron microscopy. There were no significant differences in fluorescein staining between the untreated and glaucoma eyedrop-treated groups; however, rose bengal staining and the number of inflammatory cells in the conjunctiva significantly increased after glaucoma eyedrop treatment. There was a four-fold increase in the number of dark cells in the glaucoma eyedrop-treated group compared to untreated. In contrast, in the conjunctiva of the rebamipide-treated glaucoma eyedrop group, rose bengal staining scores, the number of inflammatory cells, and the number of dark cells were decreased compared to the vehicle-treated glaucoma eyedrop group. Results from our in vivo rabbit study demonstrated that short-term use of glaucoma eyedrops induces corneal epithelium disorders at the cellular level, but that simultaneous use of rebamipide has the potential to protect and repair the ocular surface.

Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome.

PubMed

Kennedy, David P; Chandler, John W; McCulley, James P

2015-06-01

To present the ocular manifestation of 2 cases of ectrodactyly-ectodermal dysplasia-cleft syndrome, a multiple congenital anomaly syndrome caused by a single point mutation of the p63 gene that controls epidermal development and homeostasis and to present treatment options. Patient 1 presented with mild signs and symptoms of dry eye and limbal stem cell deficiency with retention of 20/30 vision. Patient 2 presented with severe signs and symptoms of limbal stem cell deficiency with diffuse corneal scarring and counting fingers vision. This second patient's course was complicated by allergic conjunctivitis and advanced steroid-induced glaucoma. The cause of visual loss in ectrodactyly-ectodermal dysplasia-cleft syndrome appears to be multifactorial and likely includes inflammation of the ocular surface, tear film abnormalities, eyelid abnormalities, and limbal stem cell deficiency. Treatment modalities including lubrication, contact lenses, and limbal stem cell transplantation are reviewed. The ophthalmic conditions seen in ectrodactyly-ectodermal dysplasia-cleft syndrome frequently lead to vision loss. Early correct diagnosis and appropriate therapy are paramount because p63 gene mutations have a critical role in maintaining the integrity of the ocular surface in the setting of limbal stem cell deficiency, especially if there are other ocular surface insults such as lid disease, meibomian gland dysfunction and toxicity from topical medications. Patients should be monitored at regular, frequent intervals; and particular attention should be taken to avoid adverse secondary effects of these conditions and medications. Copyright © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis.

PubMed

Chen, Wei; Zhang, Xiaobo; Liu, Mimi; Zhang, Jingna; Ye, Ya; Lin, Ying; Luyckx, Jacques; Qu, Jia

2009-09-01

The disaccharide trehalose is a key element involved in anhydrobiosis (the capability of surviving almost complete dehydration) in many organisms. Its presence also confers resistance to desiccation and high osmolarity in bacterial and human cells by protecting proteins and membranes from denaturation. The present study used a novel murine dry eye model induced by controlled low-humidity air velocity to determine whether topically applied trehalose could heal ocular surface epithelial disorders caused by ocular surface desiccation. In addition, the efficacy of 87.6 mM trehalose eyedrops was compared with that of 20% serum, the efficacy of which has been well documented. Mice ocular surface epithelial disorders were induced by exposure of murine eyes to continuous controlled low-humidity air velocity in an intelligently controlled environmental system (ICES) for 21 days, which accelerated the tear evaporation. The mice were then randomized into three groups: the control group received PBS (0.01 M) treatment; a second group received 87.6 mM trehalose eyedrops treatment; and the third group received mice serum eyedrops treatment. Each treatment was administered as a 10 microl dose every 6 h for 14 days. The resultant changes in corneal barrier function and histopathologic examination of cornea and conjunctiva were analyzed and the level of apoptosis on the ocular surface was assessed using active caspase-3. After 14 days of treatment, the corneal fluorescein staining area, the ruffling and desquamating cells on the apical corneal epithelium, as well as the apoptotic cells on ocular surface epithelium had significantly reduced in eyes treated with trehalose compared with those treated with serum and PBS. In contrast, after 14 days of treatment, improvements in the thickness of the corneal epithelium, the squamous metaplasia in conjunctival epithelium and the number of goblet cells of the conjunctiva were less marked in eyes treated with trehalose compared with serum. These results demonstrated that trehalose could improve the appearance of ocular surface epithelial disorders due to desiccation through suppression of apoptosis. Trehalose produces some of the same responses as serum upon topical application and can maintain corneal health.

Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye

PubMed Central

Bauskar, Aditi; Mack, Wendy J.; Mauris, Jerome; Argüeso, Pablo; Heur, Martin; Nagel, Barbara A.; Kolar, Grant R.; Gleave, Martin E.; Nakamura, Takahiro; Kinoshita, Shigeru; Moradian-Oldak, Janet; Panjwani, Noorjahan; Pflugfelder, Stephen C.; Wilson, Mark R.; Fini, M. Elizabeth; Jeong, Shinwu

2015-01-01

Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye. PMID:26402857

Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye.

PubMed

Bauskar, Aditi; Mack, Wendy J; Mauris, Jerome; Argüeso, Pablo; Heur, Martin; Nagel, Barbara A; Kolar, Grant R; Gleave, Martin E; Nakamura, Takahiro; Kinoshita, Shigeru; Moradian-Oldak, Janet; Panjwani, Noorjahan; Pflugfelder, Stephen C; Wilson, Mark R; Fini, M Elizabeth; Jeong, Shinwu

2015-01-01

Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.

Potential Role of Induced Pluripotent Stem Cells (IPSCs) for Cell-Based Therapy of the Ocular Surface

PubMed Central

Casaroli-Marano, Ricardo P.; Nieto-Nicolau, Núria; Martínez-Conesa, Eva M.; Edel, Michael; Álvarez-Palomo, Ana B.

2015-01-01

The integrity and normal function of the corneal epithelium are crucial for maintaining the cornea’s transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for bio replacement—cultured limbal epithelial transplantation (CLET) and cultured oral mucosal epithelial transplantation (COMET)—present very encouraging clinical results for treating limbal stem cell deficiency (LSCD) and restoring vision. Another emerging therapeutic approach consists of obtaining and implementing human progenitor cells of different origins in association with tissue engineering methods. The development of cell-based therapies using stem cells, such as human adult mesenchymal or induced pluripotent stem cells (IPSCs), represent a significant breakthrough in the treatment of certain eye diseases, offering a more rational, less invasive, and better physiological treatment option in regenerative medicine for the ocular surface. This review will focus on the main concepts of cell-based therapies for the ocular surface and the future use of IPSCs to treat LSCD. PMID:26239129

Differential regulation of membrane-associated mucins in the human ocular surface epithelium.

PubMed

Hori, Yuichi; Spurr-Michaud, Sandra; Russo, Cindy Leigh; Argüeso, Pablo; Gipson, Ilene K

2004-01-01

Membrane-associated mucins present in the apical cells of the ocular surface epithelium (MUC1, -4, and -16) are believed to contribute to the maintenance of a hydrated and wet-surfaced epithelial phenotype. Serum and retinoic acid (RA) have been used to treat drying ocular surface diseases. The goal of this study was to determine whether serum or RA regulates the production of membrane-associated mucins in human conjunctival epithelial cells. A telomerase-immortalized human conjunctival epithelial cell line (HCjE) was used. Cells were cultured in serum-free medium to confluence and then cultured with either 10% calf serum or with 100 nM RA for 0 to 72 hours. Conventional RT-PCR was used to determine the expression of retinoic acid receptors (RARs) and quantitative real-time PCR was used to investigate the mRNA expression of MUC1, -4, and -16. Protein levels were assayed by immunoblot analysis, using the antibodies HMFG-2, 1G8, or OC125, which are specific to MUC1, -4 and -16, respectively. To determine whether RA-associated MUC4 mRNA induction is a direct or indirect effect, HCjE cells were treated with RA and the protein synthesis inhibitor cycloheximide (1.0 microg/mL) for 12 hours. MUC1 and -16, but not -4, mRNAs were detectable in HCjE cells grown in serum-free medium. Real-time PCR revealed that MUC4 mRNA was significantly induced by serum 3 hours after its addition, and that MUC1 and MUC16 mRNA levels were significantly upregulated at 72 hours. Western blot analysis demonstrated that the MUC1, -4, and -16 proteins increased over time after addition of serum. Conventional RT-PCR analysis demonstrated that RAR-alpha and -gamma mRNA were expressed in native human conjunctival tissue as well as in the HCjE cells. Treatment with RA upregulated the expression of both MUC4 and -16 mRNA and protein, but MUC1 was unaffected. Because the protein synthesis inhibitor cycloheximide did not prevent the RA-associated induction of MUC4 mRNA, the action of RA on the MUC4 promoter may be direct. The membrane-associated mucins of the ocular surface epithelia, MUC1, -4, and -16, are differentially regulated by serum and RA in the telomerase-immortalized human conjunctival epithelial cell line. Serum derived from vessels in the conjunctiva may play an important role in mucin regulation in the ocular surface epithelia. These data also support the clinical efficacy of autologous serum and RA application in patients with ocular surface diseases. Furthermore, the data suggest that MUC4 and -16 are particularly important hydrophilic molecules involved in maintenance of a healthy ocular surface.

Lacritin and other new proteins of the lacrimal functional unit.

PubMed

McKown, Robert L; Wang, Ningning; Raab, Ronald W; Karnati, Roy; Zhang, Yinghui; Williams, Patricia B; Laurie, Gordon W

2009-05-01

The lacrimal functional unit (LFU) is defined by the 2007 International Dry Eye WorkShop as 'an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva and meibomian glands) and lids, and the sensory and motor nerves that connect them'. The LFU maintains a healthy ocular surface primarily through a properly functioning tear film that provides protection, lubrication, and an environment for corneal epithelial cell renewal. LFU cells express thousands of proteins. Over 200 new LFU proteins have been discovered in the last decade. Lacritin is a new LFU-specific growth factor in human tears that flows through ducts to target corneal epithelial cells on the ocular surface. When applied topically in rabbits, lacritin appears to increase the volume of basal tear secretion. Lacritin is one of only a handful of tear proteins preliminarily reported to be downregulated in blepharitis and in two dry eye syndromes. Computational analysis predicts an ordered C-terminal domain that binds the corneal epithelial cell surface proteoglycan syndecan-1 (SDC1) and is required for lacritin's low nanomolar mitogenic activity. The lacritin-binding site on the N-terminus of SDC1 is exposed by heparanase. Heparanase is constitutively expressed by the corneal epithelium and appears to be a normal constituent of tears. Binding triggers rapid signaling to downstream NFAT and mTOR. A wealth of other new proteins, originally designated as hypothetical when first identified by genomic sequencing, are expressed by the human LFU including: ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1 and ZMIZ2. Their demonstrated or implied roles in human genetic disease or basic cellular functions are fuel for new investigation. Addressing topical areas in ocular surface physiology with new LFU proteins may reveal interesting new biological mechanisms and help get to the heart of ocular surface dysfunction.

Clinical implications of mast cell involvement in allergic conjunctivitis.

PubMed

Elieh Ali Komi, D; Rambasek, T; Bielory, L

2018-03-01

The conjunctiva is a common site for the allergic inflammatory response due to it being highly vascularized, having constant exposure to environmental pollutants and allergenic pollens and having a unique conjunctival associated lymphoid tissue. The primary morbidity of anterior surface conjunctival disorders that include allergic conjunctivitis and tear film disorders is associated with its high frequency of involvement rather than its severity, although the more chronic forms can involve the cornea and lead to sight-threatening conditions. Ocular allergy is associated with IgE-mediated mast cell activation in conjunctival tissue leading to the release of preformed mediators including histamine and proteases and subsequent de novo formation of lipid-derived mediators and cytokines that trigger a cascade of cellular and molecular events leading to extensive migration and infiltration of inflammatory cells to the ocular surface. The trafficking of neutrophils, eosinophils, and lymphocytes to the ocular surface is due to establishing various chemokine gradients (mainly CCL11, CCL24, CCL5, MCP-3, and MCP-4), cell surface expression of adhesion molecules (such as VCAM-1 the ligand for VLA-4), and leukocyte adhesion to vascular endothelium. The release of preformed mediators underlies the acute ocular surface response while the secondary influx of inflammatory cells leading to the recruitment and activation of eosinophils and the subsequent activation of Th2 and Th1 lymphocytes at the level of the conjunctiva reflects the late-phase reaction. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Goblet Cells of the Conjunctiva: A Review of Recent Findings

PubMed Central

Gipson, Ilene K

2016-01-01

Goblet cells within the conjunctival epithelium are specialized cells that secrete mucins onto the surface of the eye. Recent research has demonstrated new characteristics of the cells, including factors influencing their differentiation, their gene products and their functions at the ocular surface. The following review summarizes the newly discovered aspects of the role of Spdef, a member of the Ets transcription factor family in conjunctival goblet cell differentiation, the newly discovered goblet cell products including claudin2, the Wnt inhibitor Frzb, and the transmembrane mucin Muc16. The current concepts of conjunctival goblet cell function, including debris removal and immune surveillance are reviewed, as are changes in the goblet cell population in ocular surface diseases. Major remaining questions regarding conjunctival cell biology are discussed. PMID:27091323

JBP485 promotes tear and mucin secretion in ocular surface epithelia

PubMed Central

Nakamura, Takahiro; Hata, Yuiko; Nagata, Maho; Yokoi, Norihiko; Yamaguchi, Shumpei; Kaku, Taiichi; Kinoshita, Shigeru

2015-01-01

Dry eye syndrome (DES), a multifactorial disease of the tears and ocular surface, is one of the most common ocular disorders. Tear film contains ocular mucins and is essential for maintaining the homeostasis of the wet ocular surface. Since there are a limited number of clinical options for the treatment of DES, additional novel treatments are needed to improve the clinical results. In this study, we found that placental extract-derived dipeptide (JBP485) clearly promoted the expression and secretion of gel-forming mucin 5ac (Muc5ac) in rabbit conjunctival epithelium. JBP485 also elevated the expression level of cell surface-associated mucins (Muc1/4/16) in rabbit corneal epithelium. The Schirmer tear test results indicated that JBP485 induced tear secretion in the rabbit model. Moreover, JBP485 clinically improved corneal epithelial damage in a mouse dry eye model. Thus, our data indicate that JBP485 efficiently promoted mucin and aqueous tear secretion in rabbit ocular surface epithelium and has the potential to be used as a novel treatment for DES. PMID:25996902

JBP485 promotes tear and mucin secretion in ocular surface epithelia.

PubMed

Nakamura, Takahiro; Hata, Yuiko; Nagata, Maho; Yokoi, Norihiko; Yamaguchi, Shumpei; Kaku, Taiichi; Kinoshita, Shigeru

2015-05-21

Dry eye syndrome (DES), a multifactorial disease of the tears and ocular surface, is one of the most common ocular disorders. Tear film contains ocular mucins and is essential for maintaining the homeostasis of the wet ocular surface. Since there are a limited number of clinical options for the treatment of DES, additional novel treatments are needed to improve the clinical results. In this study, we found that placental extract-derived dipeptide (JBP485) clearly promoted the expression and secretion of gel-forming mucin 5ac (Muc5ac) in rabbit conjunctival epithelium. JBP485 also elevated the expression level of cell surface-associated mucins (Muc1/4/16) in rabbit corneal epithelium. The Schirmer tear test results indicated that JBP485 induced tear secretion in the rabbit model. Moreover, JBP485 clinically improved corneal epithelial damage in a mouse dry eye model. Thus, our data indicate that JBP485 efficiently promoted mucin and aqueous tear secretion in rabbit ocular surface epithelium and has the potential to be used as a novel treatment for DES.

Ocular surface alterations and in vivo confocal microscopic characteristics of corneas in patients with myasthenia gravis.

PubMed

Erkan Turan, Kadriye; Kocabeyoglu, Sibel; Bekircan-Kurt, Can Ebru; Bezci, Figen; Erdem-Ozdamar, Sevim; Irkec, Murat

2018-03-01

To evaluate ocular surface alterations and characteristics of corneal basal epithelium and subbasal nerves in patients with myasthenia gravis. Myasthenia gravis patients (n = 21) and healthy controls (n = 20) were enrolled. All participants underwent ocular surface testing in the following order: tear break-up time, lissamine green staining, Schirmer I test with anesthesia, and Ocular Surface Disease Index questionnaire. The Cochet-Bonnet esthesiometer was used to measure corneal sensitivity. Basal epithelial cells and subbasal nerves were evaluated using in vivo confocal microscopy. Myasthenia gravis patients had higher Ocular Surface Disease Index score (13.9 ± 15.0 vs 1.4 ± 2.2, p < 0.001) and lissamine green staining score (0.6 ± 0.4 vs 0.2 ± 0.4, p = 0.007). Break-up time score (9.3 ± 3.0 vs 9.9 ± 1.9, p = 0.481) and Schirmer I test score (16.5 ± 9.2 vs 19.3 ± 8.4, p = 0.323) did not differ significantly. Corneal sensation was 0.4 g/mm 2 in all eyes. Patients with myasthenia gravis had lower basal epithelial cell density (3775.7 ± 938.1 vs 4983.1 ± 608.5, p < 0.001) and total nerve density (1956.1 ± 373.3 vs 2277.9 ± 405.0, p = 0.012) and higher subbasal nerve tortuosity (1.9 ± 0.8 vs 1.6 ± 0.7, p = 0.007) than controls. A significant increase in Ocular Surface Disease Index scores was found with decreasing basal epithelial cell density (rho = -0.518, p = 0.001). There was a significantly moderate negative correlation between the duration of myasthenia gravis and the number of corneal nerves (rho = -0.497, p = 0.022). Significant alterations of basal epithelial cells and subbasal nerves were demonstrated in myasthenia gravis patients although there was no difference of corneal sensitivity between myasthenia gravis patients and healthy controls. Thus, it should be borne in mind that myasthenia gravis patients deserve further evaluation with regard to ocular surface disease.

Infection and Replication of Influenza Virus at the Ocular Surface.

PubMed

Creager, Hannah M; Kumar, Amrita; Zeng, Hui; Maines, Taronna R; Tumpey, Terrence M; Belser, Jessica A

2018-04-01

Although influenza viruses typically cause respiratory tract disease, some viruses, particularly those with an H7 hemagglutinin, have been isolated from the eyes of conjunctivitis cases. Previous work has shown that isolates of multiple subtypes from both ocular and respiratory infections are capable of replication in human ex vivo ocular tissues and corneal or conjunctival cell monolayers, leaving the determinants of ocular tropism unclear. Here, we evaluated the effect of several variables on tropism for ocular cells cultured in vitro and examined the potential effect of the tear film on viral infectivity. All viruses tested were able to replicate in primary human corneal epithelial cell monolayers subjected to aerosol inoculation. The temperature at which cells were cultured postinoculation minimally affected infectivity. Replication efficiency, in contrast, was reduced at 33°C relative to that at 37°C, and this effect was slightly greater for the conjunctivitis isolates than for the respiratory ones. With the exception of a seasonal H3N2 virus, the subset of viruses studied in multilayer corneal tissue constructs also replicated productively after either aerosol or liquid inoculation. Human tears significantly inhibited the hemagglutination of both ocular and nonocular isolates, but the effect on viral infectivity was more variable, with tears reducing the infectivity of nonocular isolates more than ocular isolates. These data suggest that most influenza viruses may be capable of establishing infection if they reach the surface of ocular cells but that this is more likely for ocular-tropic viruses, as they are better able to maintain their infectivity during passage through the tear film. IMPORTANCE The potential spread of zoonotic influenza viruses to humans represents an important threat to public health. Unfortunately, despite the importance of cellular and tissue tropism to pathogenesis, determinants of influenza virus tropism have yet to be fully elucidated. Here, we sought to identify factors that limit the ability of most influenza viruses to cause ocular infection. Although ocular symptoms in humans caused by avian influenza viruses tend to be relatively mild, these infections are concerning due to the potential of the ocular surface to serve as a portal of entry for viruses that go on to establish respiratory infections. Furthermore, a better understanding of the factors that influence infection and replication in this noncanonical site may point toward novel determinants of tropism in the respiratory tract. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Release of Membrane-associated Mucins from Ocular Surface Epithelia

PubMed Central

Blalock, Timothy D.; Spurr-Michaud, Sandra J.; Tisdale, Ann S.; Gipson, Ilene K.

2008-01-01

Purpose Three membrane-associated mucins (MAMs)—MUC1, MUC4 and MUC16—are expressed at the ocular surface epithelium. Soluble forms of MAMs are detected in human tears, but the mechanisms of their release from the apical cells are unknown. The purpose of this study was to identify physiologic agents that induce ocular surface MAM release. Methods An immortalized human corneal-limbal epithelial cell line (HCLE) expressing the same MAMs as native tissue was used. An antibody specific to MUC16’s cytoplasmic tail was developed to confirm that only the extracellular domain is released into the tear fluid or culture media. Effects of agents that have been shown to be present in tears or are implicated in release/shedding of MAMs in other epithelia (neutrophil elastase, tumor necrosis factor (TNF), TNF-α-converting enzyme, and matrix metalloproteinases-7 and –9) were assessed on HCLE cells. HCLE cell surface proteins were biotinylated to measure efficiency of induced MAM release and surface restoration. Effects of induced release on surface barrier function were measured by rose bengal dye penetrance. Results MUC16 in tears and in HCLE-conditioned medium lacked the cytoplasmic tail. TNF induced release of MUC1, MUC4, and MUC16 from the HCLE surface. Matrix metalloproteinase-7 and neutrophil elastase induced release of MUC16 but not MUC1 or MUC4. Neutrophil elastase removed 68% of MUC16—78% of which was restored to the HCLE cell surface 24 hours after release. Neutrophil elastase-treated HCLE cells showed significantly reduced rose bengal dye exclusion. Conclusions Results suggest that extracellular domains of MUC1, 4, and 16 can be released from the ocular surface by agents present in tears. Neutrophil elastase and TNF present in higher amounts in dry eye patients’ tears may cause MAM release—allowing rose bengal staining. PMID:18436821

A Review of Ocular Graft-Versus-Host Disease.

PubMed

Munir, Saleha Z; Aylward, James

2017-05-01

: Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic hematopoietic stem cell transplantation, which is a potential curative therapy used in a variety of malignant or benign hematological diseases. Graft-versus-host disease primarily occurs in many organs, but most notably in the skin, lungs, gastrointestinal tract, liver, eyes, mucosa, and musculoskeletal system. Ocular manifestations of GVHD may precede other systemic GVHD findings, and it may be a poor prognosis for mortality. While all parts of the eye may be affected, ocular GVHD occurs primarily in the ocular surface. Dry eye disease or keratoconjunctivitis sicca is the most common presenting manifestation of chronic ocular GVHD. Dry eye disease in ocular GVHD is a multifactorial process, which involves destruction and fibrosis of lacrimal glands and conjunctiva, leading to tear film deficiency and instability. Depending on the severity of ocular involvement and response to treatment, ocular GVHD may cause decreased quality of life. Management of GVHD begins with prevention by understanding risk factors and by implementing prophylactic treatment after allogeneic hematopoietic stem cell transplantation. A multidisciplinary approach to the prevention and treatment of GVHD is important, and there are currently no preventive therapies available for ocular GVHD. Once diagnosed, ocular GVHD treatment strategies target ocular surface lubrication and support, tear film stabilization, inflammation reduction, and surgical intervention. The goal of this review is to define ocular GVHD and its categorical manifestations, as well as to describe the importance of comprehensive assessment, diagnosis, and ophthalmologic treatment and management of ocular GVHD with a multidisciplinary approach.

[Challenge and treatment strategy for ocular surface damage in patients with long term use of antiglaucoma drugs].

PubMed

He, Xiang-Ge

2011-02-01

Long term use of topical anti-glaucoma drugs has been shown to induce chronic conjunctivitis, superficial punctate keratitis (SPK) and dry eye symptom. Under these conditions, a loss of goblet cells in conjunctiva, epithelial squamous metaplasia and apoptosis were morphologically revealed. Benzalkonium Chloride (BKC), a most frequently used preservative in eye drops, has been found to be an important factor causing ocular surface damage. Furthermore, a big challenge for ophthalmologists is that toxic damage of medication to ocular surface tissues is mild, poor specificity, and delayed manifestation in patients, especially when coexisting with other ocular surface diseases. Impairment of ocular surface tissues greatly impacts the life quality of patients and subsequently influences compliance with glaucoma therapy. This paper emphasizes to take measures to prevent ocular surface tissue damage resulted from chronic use of topical anti-glaucoma drugs and further discusses the treatment strategy. Effective and long-lasting action drugs should always be selected for glaucomatous patients in order to decrease the frequency of topical instillation or at a more expensive medication, a fixed combination formula can be considered for glaucoma therapy. An early surgery or laser treatment is also proposed for the patients who require an IOP reduction with an existing ocular surface impairment. Future investigation and development of new medications with long-term efficacy and appropriate BKC are suggested and preservative-free or drugs with new preservative materials recommended.

Differential effect of rebamipide on transmembrane mucin biosynthesis in stratified ocular surface epithelial cells.

PubMed

Uchino, Yuichi; Woodward, Ashley M; Argüeso, Pablo

2016-12-01

Mucins are a group of highly glycosylated glycoproteins responsible for the protection of wet-surfaced epithelia. Recent data indicate that transmembrane mucins differ in their contribution to the protective function of the ocular surface, with MUC16 being the most effective barrier on the apical surface glycocalyx. Here, we investigated the role of the mucoprotective drug rebamipide in the regulation of transmembrane mucin biosynthesis using stratified cultures of human corneal and conjunctival epithelial cells. We find that the addition of rebamipide to corneal, but not conjunctival, epithelial cells increased MUC16 protein biosynthesis. Rebamipide did not affect the levels of MUC1, 4 and 20 compared to control. In these experiments, rebamipide had no effect on the expression levels of Notch intracellular domains, suggesting that the rebamipide-induced increase in MUC16 biosynthesis in differentiated corneal cultures is not regulated by Notch signaling. Overall these findings indicate that rebamipide induces the differential upregulation of MUC16 in stratified cultures of human corneal epithelial cells, which may have implications to the proper restoration of barrier function in ocular surface disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model.

PubMed

Contreras-Ruiz, L; Zorzi, G K; Hileeto, D; López-García, A; Calonge, M; Seijo, B; Sánchez, A; Diebold, Y

2013-05-01

MUC5AC is a glycoprotein with gel-forming properties, whose altered expression has been implicated in the pathogenesis of dry eye disease. The aim of our study was to achieve an efficient in vivo transfection of MUC5AC, restore its normal levels in an inflamed ocular surface and determine whether restored MUC5AC levels improve ocular surface inflammation. Cationized gelatin-based nanoparticles (NPs) loaded with a plasmid coding a modified MUC5AC protein (pMUC5AC) were instilled in healthy and experimental dry eye (EDE) mice. MUC5AC expression, clinical signs, corneal fluorescein staining and tear production were evaluated. Ocular specimens were processed for histopathologic evaluation, including goblet cell count and CD4 immunostaining. Neither ocular discomfort nor irritation was observed in vivo after NP treatment. Expression of modified MUC5AC was significantly higher in ocular surface tissue of pMUC5AC-NP-treated animals than that of controls. In healthy mice, pMUC5AC-NPs had no effect on fluorescein staining or tear production. In EDE mice, both parameters significantly improved after pMUC5AC-NP treatment. Anterior eye segment of treated mice showed normal architecture and morphology with lack of remarkable inflammatory changes, and a decrease in CD4+ T-cell infiltration. Thus, pMUC5AC-NPs were well tolerated and able to induce the expression of modified MUC5A in ocular surface tissue, leading to reduction of the inflammation and, consequently improving the associated clinical parameters, such as tear production and fluorescein staining. These results identify a potential application of pMUC5AC-NPs as a new therapeutic modality for the treatment of dry eye disease.

[Optimization of benzalkonium chloride concentration in 0.0015% tafluprost ophthalmic solution from the points of ocular surface safety and preservative efficacy].

PubMed

Asada, Hiroyuki; Takaoka-Shichijo, Yuko; Nakamura, Masatsugu; Kimura, Akio

2010-06-01

Optimization of benzalkonium chloride (alkyl dimethylbenzylammonium chloride: BAK) concentration as preservative in 0.0015% tafluprost ophthalmic solution (Tapros 0.0015% ophthalmic solution), an anti-glaucoma medicine, was examined from the points of ocular surface safety and preservative efficacy. BAKC(12), which is dodecyl dimethylbenzylammonium chloride, and BAKmix, which is the mixture of dodecyl, tetradecyl and hexadecyl dimethylbenzylammonium chloride were used in this study. The effects of BAKC(12) concentrations and the BAK types, BAKC(12) and BAKmix, in tafluprost ophthalmic solution on ocular surface safety were evaluated using the in vitro SV 40-immobilized human corneal epithelium cell line (HCE-T). Following treatments of Tafluprost ophthalmic solutions with BAKC(12), its concentration dependency was observed on cell viability of HCE-T. The cell viability of HCE-T after treatment of these solutions with 0.001% to 0.003% BAKC(12) for 5 minutes were the same level as that after treatment of the solution without BAK. Tafluprost ophthalmic solution with 0.01% BAKC(12) was safer for the ocular surface than the same solution with 0.01% BAKmix. Preservatives-effectiveness tests of tafluprost ophthalmic solutions with various concentrations of BAKC(12) were performed according to the Japanese Pharmacopoeia (JP), and solutions with more than 0.0005% BAKC(12) conformed to JP criteria. It was concluded that 0.0005% to 0.003% of BAKC(12) in tafluprost ophthalmic solution was optimal, namely, well-balanced from the points of ocular surface safety and preservative efficacy.

[Hyperosmolarity: Intracellular effects and implication in dry eye disease].

PubMed

Warcoin, E; Clouzeau, C; Brignole-Baudouin, F; Baudouin, C

2016-09-01

Dry eye disease is a multifactorial disease affecting the lacrimal functional unit and which has a significant impact on the quality of life of patients. This pathology works as a vicious circle at the ocular surface in which hyperosmolarity of the tear film plays a key role. This review intends to describe the different reported intracellular effects induced by hyperosmolarity in cells: alteration of cytoskeleton, cell cycle slowdown, adaptation mechanisms triggered as restoration of cell volume and accumulation of compatible osmolytes, the crucial role of the osmoprotectant factor Nuclear Factor of the Activated T cells-5 (NFAT5), apoptosis, as well as oxidative stress and inflammatory responses caused by this particular condition. Reported effects of hyperosmolarity in the experimental studies specific of dry eye disease concerning ocular surface cells will be described in parallel. Indeed, these data allow to understand a part of the pathophysiology of the disease, and specially the links between tear hyperosmolarity and inflammation of the ocular surface, the second key of the pathology phenomenon. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An impression cytology based study of ocular surface in an urban population.

PubMed

Mukhopadhyay, Somnath; Dutta, Jayanta; Mitra, Jayati; Prakash, Ratnesh; Datta, Himadri

2013-04-01

To assess the health of ocular surface in a defined urban population, conjunctival goblet cell density and degree of surface squamous metaplasia were utilized as study tools. Two thousand names of those aged between 20 and 79 years from the 2006 electoral register in ward number 63 of Kolkata Corporation area were initially selected. Normal healthy human volunteers without any history of ocular surface disorder were recruited and divided into five age-groups. Impression cytology samples were obtained from interpalpebral part of bulbar conjunctiva from all the participants fixated and stained by a single observer. A stratified, clustered, disproportionate, random sampling method was used. The software used in the statistical analysis was EPI Info. The tests applied were t test and ANOVA. A variation in the number of goblet cells according to gender (women having less cells) and age (20-30 years group having the highest number of cells) was found. Those working outdoors were found to have fewer goblet cells compared to those who stay indoors. The majority of the people had grade 1 cytological appearance in both males and females. There was no statistically significant difference in Nelson's grading with age. People using coal and kerosene to cook were found to have a smaller goblet cell density than those who cooked on LPG or those who did not cook at all. Besides age and sex, environmental factors like the method of cooking and occupational variables (like outdoor activity, prolonged period of computer use, etc.) modify the health of the ocular surface. The results of this study will help put these findings into perspective as public health problems.

Ocular surface changes in limbal stem cell deficiency caused by chemical injury: a histologic study of excised pannus from recipients of cultured corneal epithelium.

PubMed

Fatima, A; Iftekhar, G; Sangwan, V S; Vemuganti, G K

2008-09-01

To report histopathologic changes of the ocular surface pannus in patients with severe limbal stem cell deficiency (LSCD). Corneal and conjunctival pannus tissues from 29 patients undergoing ocular reconstruction with cultured limbal cell transplantation were included. The medical records of these patients were reviewed for demographics, aetiologic diagnosis, type of injury, interval between the initial insult and excision of pannus, and medical history involving human amniotic membrane (HAM) or limbal transplantation. The paraffin-embedded tissues were reviewed for epithelial changes, type-degree of fibrosis, degenerative changes, vascular changes, conjunctivalization of corneal surface, and evidence of residual HAM. We attempted a clinicopathologic correlation to understand the pathogenesis of pannus formation in LSCD. The 29 tissues were from 29 eyes of patients with primary aetiology of chemical burn in 89.6% (undetermined in 10.4%) of cases. The pannus showed epithelial hyperplasia in 62%, active fibrosis in 66%, severe inflammation in 21%, giant cell reaction in 28%, and stromal calcification in 14% cases. Goblet cells were seen over the cornea in 64% cases; their absence was associated with squamous metaplasia of the conjunctiva and with long duration of insult. Evidence of residual HAM was noted in 42% cases. The commonest cause of severe LSCD is alkali-induced injury. Goblet cells over the cornea were seen in 60% of cases. HAM used for ocular surface reconstruction could persist for long periods within the corneal pannus, thus raising the need for further studies with long-term follow-up.

Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease.

PubMed

Coursey, Terry G; Gandhi, Niral B; Volpe, Eugene A; Pflugfelder, Stephen C; de Paiva, Cintia S

2013-01-01

CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.

Chemokine Receptors CCR6 and CXCR3 Are Necessary for CD4+ T Cell Mediated Ocular Surface Disease in Experimental Dry Eye Disease

PubMed Central

Coursey, Terry G.; Gandhi, Niral B.; Volpe, Eugene A.; Pflugfelder, Stephen C.; de Paiva, Cintia S.

2013-01-01

CD4+ T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4+ T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4+ T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4+ T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease. PMID:24223818

PRGF exerts more potent proliferative and anti-inflammatory effects than autologous serum on a cell culture inflammatory model.

PubMed

Anitua, E; Muruzabal, F; de la Fuente, M; Riestra, A; Merayo-Lloves, J; Orive, G

2016-10-01

Ocular graft versus host disease (oGVHD) is part of a systemic inflammatory disease that usually affects ocular surface tissues manifesting as a dry eye syndrome. Current treatments provide unsatisfactory results. Blood-derived products, like plasma rich in growth factors (PRGF) emerge as a potential therapy for this disease. The purpose of this study was to evaluate the tissue regeneration and anti-inflammatory capability of PRGF, an autologous platelet enriched plasma eye-drop, compared to autologous serum (AS) obtained from oGVHD patients on ocular surface cells cultured in a pro-inflammatory environment. PRGF and AS were obtained from four GVHD patients. Cell proliferation and inflammation markers, intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2), were measured in corneal and conjunctival fibroblastic cells cultured under pro-inflammatory conditions and after treatment with PRGF or AS eye drops. Moreover, cell proliferation increased after treatment with PRGF and AS, though this enhancement in the case of keratocytes was significantly higher with PRGF. PRGF eye drops showed a significant reduction of both inflammatory markers with respect to the initial inflammatory situation and to the AS treatment. Our results concluded that PRGF exerts more potent regenerative and anti-inflammatory effects than autologous serum on ocular surface fibroblasts treated with pro-inflammatory IL-1β and TNFα. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lacritin and Other New Proteins of the Lacrimal Functional Unit

PubMed Central

McKown, Robert L.; Wang, Ningning; Raab, Ronald W.; Karnati, Roy; Zhang, Yinghui; Williams, Patricia B.; Laurie, Gordon W.

2009-01-01

The lacrimal functional unit (LFU) is defined by the 2007 International Dry Eye WorkShop as ‘an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva and meibomian glands) and lids, and the sensory and motor nerves that connect them’. The LFU maintains a healthy ocular surface primarily through a properly functioning tear film that provides protection, lubrication, and an environment for corneal epithelial cell renewal. LFU cells express thousands of proteins. Over two hundred new LFU proteins have been discovered in the last decade. Lacritin is a new LFU-specific growth factor in human tears that flows through ducts to target corneal epithelial cells on the ocular surface. When applied topically in rabbits, lacritin appears to increase the volume of basal tear secretion. Lacritin is one of only a handful of tear proteins preliminarily reported to be downregulated in blepharitis and in two dry eye syndromes. Computational analysis predicts an ordered C-terminal domain that binds the corneal epithelial cell surface proteoglycan syndecan-1 (SDC1) and is required for lacritin’s low nanomolar mitogenic activity. The lacritin binding site on the N-terminus of SDC1 is exposed by heparanase. Heparanase is constitutively expressed by the corneal epithelium and appears to be a normal constituent of tears. Binding triggers rapid signaling to downstream NFAT and mTOR. A wealth of other new proteins, originally designated as hypothetical when first identified by genomic sequencing, are expressed by the human LFU including: ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1 and ZMIZ2. Their demonstrated or implied roles in human genetic disease or basic cellular functions are fuel for new investigation. Addressing topical areas in ocular surface physiology with new LFU proteins may reveal interesting new biological mechanisms and help get to the heart of ocular surface dysfunction. PMID:18840430

Efficacy of a New Ocular Surface Modulator in Restoring Epithelial Changes in an In Vitro Model of Dry Eye Syndrome.

PubMed

Barabino, Stefano; De Servi, Barbara; Aragona, Salvatore; Manenti, Demetrio; Meloni, Marisa

2017-03-01

So far tear substitutes have demonstrated a limited role in restoring ocular surface damage in dry eye syndrome (DES). The aim of this study was to assess the efficacy of a new ocular surface modulator in an in vitro model of human corneal epithelium (HCE) damaged by severe osmotic stress mirroring the features of dry eye conditions. A reconstructed HCE model challenged by the introduction of sorbitol in the culture medium for 16 h was used to induce an inflammatory pathway and to impair the tight junctions integrity determining a severe modification of the superficial layer ultrastructure. At the end of the overnight stress period in the treated HCE series, 30 μl of the ocular surface modulator (T-LysYal, Sildeha, Switzerland) and of hyaluronic acid (HA) in the control HCE series were applied for 24 h. The following parameters were quantified: scanning electron microscopy (SEM), trans-epithelial electrical resistance (TEER), immunofluorescence analysis of integrin β1 (ITG-β1), mRNA expression of Cyclin D-1 (CCND1), and ITG-β1. In the positive control after the osmotic stress the HCE surface damage was visible at the ultrastructural level with loss of cell-cell interconnections, intercellular matrix destruction, and TEER reduction. After 24 h of treatment with T-LysYal, HCE showed a significant improvement of the ultrastructural morphological organization and increased expression of ITG-β1 at the tissue level when compared to positive and control series. A significant increase of mRNA expression for ITG-β1 and CCND1 was shown in the HA-treated cells compared to T-LysYal. TEER measurement showed a significant reduction in all groups after 16 h without modifications after the treatment period. This study has shown the possibility of a new class of agents denominated ocular surface modulators to restore corneal cells damaged by dry eye conditions. Further in vivo studies are certainly necessary to confirm these results.

Mechanisms Involved in Injury and Repair of the Murine Lacrimal Gland: Role of Programmed Cell Death and Mesenchymal Stem Cells

PubMed Central

Zoukhri, Driss

2011-01-01

The non-keratinized epithelia of the ocular surface are constantly challenged by environmental insults, such as smoke, dust, and airborne pathogens. Tears are the sole physical protective barrier for the ocular surface. Production of tears in inadequate quantity or of inadequate quality results in constant irritation of the ocular surface, leading to dry eye disease, also referred to as keratoconjunctivitis sicca (KCS). Inflammation of the lacrimal gland, such as occurs in Sjögren’s syndrome, sarcoidosis, chronic graft versus-host disease, and other pathological conditions, results in inadequate secretion of the aqueous layer of the tear film, and is a leading cause of dry eye disease. The hallmarks of lacrimal gland inflammation are the presence of immune cell infiltrates, loss of acinar epithelial cells (the secreting cells), and increased production of proinflammatory cytokines. To date, the mechanisms leading to acinar cell loss and the associated decline in lacrimal gland secretion are still poorly understood. It is also not understood why the remaining lacrimal gland cells are unable to proliferate in order to regenerate a functioning lacrimal gland. This article reviews recent advances in exocrine tissue injury and repair, with emphasis on the roles of programmed cell death and stem/progenitor cells. PMID:20427009

Comparing goblet cell densities in patients wearing disposable hydrogel contact lenses versus silicone hydrogel contact lenses in an extended-wear modality.

PubMed

Lievens, Christopher W; Connor, Charles G; Murphy, Heather

2003-10-01

The current study evaluates the response of the ocular surface to extended contact lens wear by comparing a new silicone hydrogel lens to an ACUVUE 2 lens. Twenty subjects with an average age of 28 years were randomly assigned to a fitting with ACUVUE 2 or PureVision lenses. Ocular surface assessment by impression cytology was performed at baseline and for the 6 months after initiation of lens wear. Although goblet cell density significantly increased with wear time, no statistically significant difference was observed between the contact lens groups. The average baseline goblet cell percentages were as follows: ACUVUE 2 group, 1.44; PureVision group, 1.11. The 6-month averages were as follows: ACUVUE 2 group, 3.16; PureVision group, 2.22. It appears that silicone hydrogel lenses may be slightly less irritating to the ocular surface than lenses not containing silicone. This could be a promising indicator for successful 30-day continuous wear.

Glycobiology of ocular angiogenesis

PubMed Central

Markowska, Anna I; Cao, Zhiyi; Panjwani, Noorjahan

2014-01-01

Ocular neovascularization can affect almost all the tissues of the eye: the cornea, the iris, the retina, and the choroid. Pathological neovascularization is the underlying cause of vision loss in common ocular conditions such as diabetic retinopathy, retinopathy of prematurity and age-related macular neovascularization. Glycosylation is the most common covalent posttranslational modification of proteins in mammalian cells. A growing body of evidence demonstrates that glycosylation influences the process of angiogenesis and impacts activation, proliferation, and migration of endothelial cells as well as the interaction of angiogenic endothelial cells with other cell types necessary to form blood vessels. Recent studies have provided evidence that members of the galectin class of β-galactoside-binding proteins modulate angiogenesis by novel carbohydrate-based recognition systems involving interactions between glycans of angiogenic cell surface receptors and galectins. This review discusses the significance of glycosylation and the role of galectins in the pathogenesis of ocular neovascularization. PMID:25108228

Phototoxic effects of an operating microscope on the ocular surface and tear film.

PubMed

Hwang, Hyung Bin; Kim, Hyun Seung

2014-01-01

We evaluated light exposure-induced dry eye syndrome by investigating the phototoxic effects of an operating microscope on the ocular surface and tear film in rabbits. Sixty eyes of 30 rabbits were divided into 3 groups based on the intensity of light exposure received from an operating microscope: Control group, no exposure to light; group A, 40,000-lx intensity for 30 minutes; and group B, 100,000-lx intensity for 30 minutes. To evaluate the potential damage to the ocular surface and tear film, Schirmer tests, rose bengal staining, and conjunctival impression cytology were performed before the light exposure and at 1, 3, and 5 days afterward. In addition, the expression of interleukin 1-beta was analyzed in tear samples. The expression of mucin 5AC was evaluated using immunofluorescence staining, and periodic acid-Schiff staining was conducted on conjunctival tissues. Corneal and conjunctival tissues were observed by means of electron microscopy. Potential damage to the ocular surface and tear film was found in the light-exposed groups as evidenced by decreased aqueous tear production, devitalized corneal and conjunctival epithelial cells, squamous metaplasia of conjunctival epithelial cells, decreased conjunctival goblet cell density, decreased expression of mucin 5AC, ultrastructural cellular damage to corneal and conjunctival tissues, and increased interleukin 1-beta expression in tears. This damage was more noticeable in group B than in group A (P < 0.05). Light exposure from an operating microscope had phototoxic effects on the ocular surface and tear film in this in vivo experiment. These changes seemed to intensify as the intensity of the light increased. Therefore, excessive light exposure during ophthalmic procedures could be a pathogenic factor in dry eye syndrome after a surgery is performed.

Glycobiology of the ocular surface: Mucins and lectins

PubMed Central

Argüeso, Pablo

2013-01-01

Glycosylation is an important and common form of posttranscriptional modification of proteins in cells. A vast array of biological functions has been ascribed to glycans during the last decade thanks to a rapid evolution in glycomic technologies. Glycogenes highly expressed at the human ocular surface include families of glycosyltransferases, proteoglycans, glycan degradation proteins, as well as mucins and carbohydrate-binding proteins such as the galectins. On the apical glycocalyx, mucin O-glycans promote boundary lubrication, prevent bacterial adhesion and endocytic activity, and maintain epithelial barrier function through interactions with galectins. The emerging roles attributed to glycans are contributing to the appreciation of their biological capabilities at the ocular surface. PMID:23325272

The cellular mechanisms of dry eye: from pathogenesis to treatment.

PubMed

Mantelli, Flavio; Massaro-Giordano, Mina; Macchi, Ilaria; Lambiase, Alessandro; Bonini, Stefano

2013-12-01

Dry eye is a complex disease characterized by changes in the ocular surface epithelia related to reduced quality and/or quantity of tears, inflammatory reaction, and impairment of ocular surface sensitivity. It has recently been proposed that increased tear osmolarity represents a main trigger to the altered cellular mechanisms leading to epithelial damage in dry eye. However, dry eye pathogenesis is multifactorial, with cytotoxic inflammatory mediators, altered lacrimal gland secretion and nerve function, squamous metaplasia of the conjunctival epithelium and decrease of goblet cells density, all playing a role in a detrimental loop that perpetuates and worsens damage to the corneal and conjunctival epithelia. Current topical treatments for dry eye patients include the use of lubricants and anti-inflammatory drugs. However, lubricants only improve symptoms temporarily, and chronic use of topical steroids is associated to severe ocular side effects such as cataract and glaucoma. The deeper understanding of the cellular mechanisms that are altered in dry eye is opening novel perspectives for patients and physicians, who are seeking treatments capable not only of improving symptoms but also of restoring the homeostasis of the ocular surface. In this review, we will focus on novel anti-inflammatory agents and on nerve growth factor, a neurotrophin that is altered in dry eye and has been suggested as a main player in the neuroimmune cross-talk of the ocular surface as well as in the stimulation of corneal sensitivity, epithelial proliferation and differentiation, and stimulation of mucin production by goblet cells. J. Cell. Physiol. 228: 2253-2256, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Mucin characteristics of human corneal-limbal epithelial cells that exclude the rose bengal anionic dye.

PubMed

Argüeso, Pablo; Tisdale, Ann; Spurr-Michaud, Sandra; Sumiyoshi, Mika; Gipson, Ilene K

2006-01-01

Rose bengal is an organic anionic dye used to assess damage of the ocular surface epithelium in ocular surface disease. It has been proposed that mucins have a protective role, preventing rose bengal staining of normal ocular surface epithelial cells. The current study was undertaken to evaluate rose bengal staining in a human corneal-limbal epithelial (HCLE) cell line known to produce and glycosylate membrane-associated mucins. HCLE cells were grown to confluence in serum-free medium and switched to DMEM/F12 with 10% serum to promote differentiation. Immunolocalization of the membrane-associated mucins MUC1 and MUC16 and the T-antigen carbohydrate epitope was performed with the monoclonal antibodies HMFG-2 and OC125 and jacalin lectin, respectively. To assess dye uptake, cultures were incubated for 5 minutes with 0.1% rose bengal and photographed. To determine whether exclusion of negatively charged rose bengal requires a negative charge at the cell surface, cells were incubated with fluoresceinated cationized ferritin. The effect of hyperosmotic stress on rose bengal staining in vitro was evaluated by increasing the ion concentration (Ca+2 and Mg+2) in the rose bengal uptake assay. The cytoplasm and nucleus of confluent HCLE cells cultured in media without serum, lacking the expression of MUC16 but not MUC1, as well as human corneal fibroblasts, which do not express mucins, stained with rose bengal. Culture of HCLE cells in medium containing serum resulted in the formation of islands of stratified cells that excluded rose bengal. Apical cells of the stratified islands produced MUC16 and the T-antigen carbohydrate epitope on their apical surfaces. Colocalization experiments demonstrated that fluoresceinated cationized ferritin did not bind to these stratified cells, indicating that rose bengal is excluded from cells that lack negative charges. Increasing the amounts of divalent cations in the media reduced the cellular area protected against rose bengal uptake. These results indicate that stratification and differentiation of corneal epithelial cells, as measured by the capacity to produce the membrane-associated mucin MUC16 and the mucin-associated T-antigen carbohydrate on their apical surfaces provide protection against rose bengal penetrance in vitro and suggest a role for membrane-associated mucins and their oligosaccharides in the protection of ocular surface epithelia.

Mucin Characteristics of Human Corneal-Limbal Epithelial Cells that Exclude the Rose Bengal Anionic Dye

PubMed Central

Argüeso, Pablo; Tisdale, Ann; Spurr-Michaud, Sandra; Sumiyoshi, Mika; Gipson, Ilene K.

2005-01-01

Purpose Rose bengal is an organic anionic dye used to assess damage of the ocular surface epithelium in ocular surface disease. It has been proposed that mucins have a protective role, preventing rose bengal staining of normal ocular surface epithelial cells. The current study was undertaken to evaluate rose bengal staining in a human corneal-limbal epithelial (HCLE) cell line known to produce and glycosylate membrane-associated mucins. Methods HCLE cells were grown to confluence in serum-free medium and switched to DMEM/F12 with 10% serum to promote differentiation. Immunolocalization of the membrane-associated mucins MUC1 and MUC16 and the T-antigen carbohydrate epitope was performed with the monoclonal antibodies HMFG-2 and OC125 and jacalin lectin, respectively. To assess dye uptake, cultures were incubated for 5 minutes with 0.1% rose bengal and photographed. To determine whether exclusion of negatively charged rose bengal requires a negative charge at the cell surface, cells were incubated with fluoresceinated cationized ferritin. The effect of hyperosmotic stress on rose bengal staining in vitro was evaluated by increasing the ion concentration (Ca+2 and Mg+2) in the rose bengal uptake assay. Results The cytoplasm and nucleus of confluent HCLE cells cultured in media without serum, lacking the expression of MUC16 but not MUC1, as well as human corneal fibroblasts, which do not express mucins, stained with rose bengal. Culture of HCLE cells in medium containing serum resulted in the formation of islands of stratified cells that excluded rose bengal. Apical cells of the stratified islands produced MUC16 and the T-antigen carbohydrate epitope on their apical surfaces. Colocalization experiments demonstrated that fluoresceinated cationized ferritin did not bind to these stratified cells, indicating that rose bengal is excluded from cells that lack negative charges. Increasing the amounts of divalent cations in the media reduced the cellular area protected against rose bengal uptake. Conclusions These results indicate that stratification and differentiation of corneal epithelial cells, as measured by the capacity to produce the membrane-associated mucin MUC16 and the mucin-associated T-antigen carbohydrate on their apical surfaces provide protection against rose bengal penetrance in vitro and suggest a role for membrane-associated mucins and their oligosaccharides in the protection of ocular surface epithelia. PMID:16384952

Release of complement regulatory proteins from ocular surface cells in infections.

PubMed

Cocuzzi, E; Guidubaldi, J; Bardenstein, D S; Chen, R; Jacobs, M R; Medof, E M

2000-11-01

The decay accelerating factor (DAF or CD55) and the membrane inhibitor of reactive lysis (MIRL or CD59), two complement regulatory proteins that protect self cells from autologous complement-mediated injury, are attached to corneal and cqonjunctival epithelial cells by glycosylphos-phatidylinositol (GPI) anchors. We sought to 1) determine the frequency with which bacteria recovered from patients with infections of the eye elaborate factors that can remove these surface proteins from ocular cells, 2) determine the spectrum of bacteria from other sites that have similar effects, and 3) establish the time interval required for reconstitution of the two regulators. Culture supernatants of 18 ocular isolates [P. aeruginosa (n = 3), S. marcescens (n = 1), S. epidermidis (n = 9), and S. aureus (n = 5)], and > 100 other clinical specimens isolated in the hospital's microbiology laboratory [P. mirabilis (n = 1), S. aureus (n = 65), S. epidermidis (n = 24), B. cereus (n = 12), H. influenzae (n = 15), and Enterobacter sp. (n = 21)] were incubated at 37 degrees C for various times with conjunctival epithelial cells, conjunctival fibroblasts or HeLa cells and the release of DAF and CD59 proteins from the surfaces of the cells analyzed by 2-site immunoradiometric assays and by Western blotting. The kinetics of recovery of DAF and CD59 expression on the cells was measured by flow cytometry. DAF and/or CD59 release from the cell monolayers varied from < 5% to > 99% at as much as a 1:81 dilution of the supernatant from some bacteria. On conjunctival epithelial cells, more than 8 hr was required for 44% recovery of DAF expression and for 50% recovery of CD59 expression. Bacteria produce phospholipases and/or other enzymes which can efficiently remove DAF and CD59 from ocular cell surfaces. This phenomenon may correlate with their in vivo pathogenicity.

Mucosal tolerance disruption favors disease progression in an extraorbital lacrimal gland excision model of murine dry eye.

PubMed

Guzmán, Mauricio; Keitelman, Irene; Sabbione, Florencia; Trevani, Analía S; Giordano, Mirta N; Galletti, Jeremías G

2016-10-01

Dry eye is a highly prevalent immune disorder characterized by a dysfunctional tear film and a Th1/Th17 T cell response at the ocular surface. The specificity of these pathogenic effector T cells remains to be determined, but auto-reactivity is considered likely. However, we have previously shown that ocular mucosal tolerance to an exogenous antigen is disrupted in a scopolamine-induced murine dry eye model and that it is actually responsible for disease progression. Here we report comparable findings in an entirely different murine model of dry eye that involves resection of the extraorbital lacrimal glands but no systemic muscarinic receptor blockade. Upon ocular instillation of ovalbumin, a delayed breakdown in mucosal tolerance to this antigen was observed in excised but not in sham-operated mice, which was mediated by interferon γ- and interleukin 17-producing antigen-specific T cells. Consistently, antigen-specific regulatory T cells were detectable in sham-operated but not in excised mice. As for other models of ocular surface disorders, epithelial activation of the NF-κB pathway by desiccating stress was determinant in the mucosal immune outcome. Underscoring the role of mucosal tolerance disruption in dry eye pathogenesis, its prevention by a topical NF-κB inhibitor led to reduced corneal damage in excised mice. Altogether these results show that surgically originated desiccating stress also initiates an abnormal Th1/Th17 T cell response to harmless exogenous antigens that reach the ocular surface. This event might actually contribute to corneal damage and challenges the conception of dry eye as a strictly autoimmune disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ocular Pharmacology of Tear Film, Dry Eye, and Allergic Conjunctivitis.

PubMed

Gulati, Shilpa; Jain, Sandeep

2017-01-01

Dry Eye Disease (DED) is "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear-film instability with potential damage to the ocular surface." DED comprises two etiologic categories: aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE). Diagnostic workup of DED should include clinical history, symptom questionnaire, fluorescein TBUT, ocular surface staining grading, Schirmer I/II, lid and meibomian pathology, meibomian expression, followed by other available tests. New diagnostic tests employ the Oculus Keratograph, which performs non-invasive tear-film analysis and a bulbar redness (BR). The TearLab Osmolarity Test enables rapid clinical evaluation of tear osmolarity. Lipiview is a recently developed diagnostic tool that uses interferometry to quantitatively evaluate tear-film thickness. In DED, epithelial and inflammatory cells produce a variety of inflammatory mediators. A stagnant tear film and decreased concentration of mucin result in the accumulation of inflammatory factors that can penetrate tight junctions and cause epithelial cell death. DED treatment algorithms are based on severity of clinical signs and symptoms, and disease etiology. Therapeutic approaches include lubricating artificial tears and immunomodulatory agents.

Comparing the Effects of Particulate Matter on the Ocular Surfaces of Normal Eyes and a Dry Eye Rat Model.

PubMed

Han, Ji Yun; Kang, Boram; Eom, Youngsub; Kim, Hyo Myung; Song, Jong Suk

2017-05-01

To compare the effect of exposure to particulate matter on the ocular surface of normal and experimental dry eye (EDE) rat models. Titanium dioxide (TiO2) nanoparticles were used as the particulate matter. Rats were divided into 4 groups: normal control group, TiO2 challenge group of the normal model, EDE control group, and TiO2 challenge group of the EDE model. After 24 hours, corneal clarity was compared and tear samples were collected for quantification of lactate dehydrogenase, MUC5AC, and tumor necrosis factor-α concentrations. The periorbital tissues were used to evaluate the inflammatory cell infiltration and detect apoptotic cells. The corneal clarity score was greater in the EDE model than in the normal model. The score increased after TiO2 challenge in each group compared with each control group (normal control vs. TiO2 challenge group, 0.0 ± 0.0 vs. 0.8 ± 0.6, P = 0.024; EDE control vs. TiO2 challenge group, 2.2 ± 0.6 vs. 3.8 ± 0.4, P = 0.026). The tear lactate dehydrogenase level and inflammatory cell infiltration on the ocular surface were higher in the EDE model than in the normal model. These measurements increased significantly in both normal and EDE models after TiO2 challenge. The tumor necrosis factor-α levels and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were also higher in the EDE model than in the normal model. TiO2 nanoparticle exposure on the ocular surface had a more prominent effect in the EDE model than it did in the normal model. The ocular surface of dry eyes seems to be more vulnerable to fine dust of air pollution than that of normal eyes.

Penetration of mucoadhesive chitosan-dextran sulfate nanoparticles into the porcine cornea.

PubMed

Chaiyasan, Wanachat; Praputbut, Sakonwun; Kompella, Uday B; Srinivas, Sangly P; Tiyaboonchai, Waree

2017-01-01

Topical application of drugs to the eyes suffers from poor bioavailability at the ocular surface and in the anterior chamber. This is due to rapid clearance of the drug because of tear secretion and outflow. This study has investigated mucoadhesive and penetration characteristics of chitosan-dextran sulfate nanoparticles (CDNs), prepared by polyelectrolyte complexation technique, following topical administration to the ocular surface. Topical FITC-labeled CDNs (FCDNs; mean size of 400nm and a surface charge of +48mV) were retained on the porcine ocular surface for more than 4h. Topical FCDNs were partially endocytosed into porcine corneal epithelial cells via a clathrin-dependent pathway. After 6h of topical FCDNs, particles accumulated in the corneal epithelium but not found in the corneal stroma. When epithelium was removed, FCDNs penetrated the stroma. Thus, CDNs are potentially useful for drug/gene delivery to the ocular surface and to stroma when epithelium is damaged. Copyright © 2016 Elsevier B.V. All rights reserved.

Improved impression cytology techniques for the immunopathological diagnosis of superficial viral infections

PubMed Central

Thiel, M; Bossart, W; Bernauer, W

1997-01-01

BACKGROUND—For epidemiological and therapeutic reasons early diagnosis of superficial viral infections is crucial. Conventional microbiological techniques are expensive, time consuming, and not sufficiently sensitive. In this study impression cytology techniques were evaluated to analyse their diagnostic potential in viral infections of the ocular surface.
METHOD—A Biopore membrane device instead of the original impression cytology technique was used to allow better quality and handling of the specimens. The impressions were processed, using monoclonal antibodies and immunoperoxidase or immunofluorescence techniques to assess the presence of herpes simplex virus, varicella zoster virus, or adenovirus antigens. Ocular surface specimens from healthy individuals (n=10) and from patients with suspected viral surface disease (n=19) were studied. Infected and non-infected cell cultures served as controls.
RESULTS—This modified technique of impression cytology allowed the collection of large conjunctival and corneal epithelial cell layers with excellent morphology. Immunocytological staining of these samples provided diagnostic results for all three viruses in patients with viral surface disease.
CONCLUSIONS—The use of Biopore membrane devices for the collection of ocular surface epithelia offers new diagnostic possibilities for external eye diseases. Immunopathological methods that are applied directly on these membrane devices can provide virological results within 1-4 hours. This contributes considerably to the clinical management of patients with infectious diseases of the ocular surface.

 PMID:9505824

Dry Eye as a Mucosal Autoimmune Disease

PubMed Central

Stern, Michael E.; Schaumburg, Chris S.; Pflugfelder, Stephen C.

2013-01-01

Dry eye is a common ocular surface inflammatory disease that significantly affects quality of life. Dysfunction of the lacrimal function unit (LFU) alters tear composition and breaks ocular surface homeostasis, facilitating chronic inflammation and tissue damage. Accordingly, the most effective treatments to date are geared towards reducing inflammation and restoring normal tear film. The pathogenic role of CD4+ T cells is well known, and the field is rapidly realizing the complexity of other innate and adaptive immune factors involved in the development and progression of disease. The data support the hypothesis that dry eye is a localized autoimmune disease originating from an imbalance in the protective immunoregulatory and proinflammatory pathways of the ocular surface. PMID:23360156

Comparison of efficacy and ocular surface toxicity of topical preservative-free methylprednisolone and preserved prednisolone in the treatment of acute anterior uveitis.

PubMed

Hedayatfar, Alireza; Hashemi, Hassan; Asgari, Soheila; Chee, Soon-Phaik

2014-04-01

The aim of this study was to compare the antiinflammatory effect and ocular surface toxicity of topical nonpreserved methylprednisolone sodium succinate 1% and preserved prednisolone acetate suspension 1% for the management of acute anterior uveitis (AAU). In this prospective, randomized, investigator-masked, comparative clinical trial, patients with mild-to-moderate noninfectious AAU were assigned randomly to receive either hourly nonpreserved methylprednisolone 1% (group A) or preserved prednisolone 1% (group B) eye drops followed by a 2-week tapering regimen. Anterior chamber cells and flare were clinically evaluated for the objective comparison of the antiinflammatory effect. The main outcome measure was the percentage of patients with a resolution of inflammation (anterior chamber cells <1+) on day 14. Ocular surface toxicity was assessed by means of the corneal fluorescein staining score, tear breakup time, Schirmer I test, and questionnaire-based grading of ocular discomfort parameters. Seventy-two eyes of 68 patients were studied, of which 38 eyes were enrolled in group A and 34 eyes were enrolled in group B. On day 14, 76.3% of the patients in group A had resolution of inflammation compared with 70.6% of the patients in group B, proving noninferiority (χ = 0.303, P = 0.582). The mean anterior chamber cell grade reduction for patients in group A was similar to that in group B (2.52 vs. 2.86, respectively; P = 0.92). Group A patients showed significantly lower corneal fluorescein staining scores (P < 0.001) and reported milder subjective ocular discomfort (0.55 vs. 1.43, P = 0.01) as compared with group B. Both preparations demonstrated equal antiinflammatory effects for the treatment of AAU. Nonpreserved methylprednisolone eye drops exhibited a significantly lower ocular surface toxicity profile and milder subjective discomfort when compared with that exhibited by preserved prednisolone.

The Ocular Surface Chemical Burns

PubMed Central

Baradaran-Rafii, Alireza; Djalilian, Ali R.

2014-01-01

Ocular chemical burns are common and serious ocular emergencies that require immediate and intensive evaluation and care. The victims of such incidents are usually young, and therefore loss of vision and disfigurement could dramatically affect their lives. The clinical course can be divided into immediate, acute, early, and late reparative phases. The degree of limbal, corneal, and conjunctival involvement at the time of injury is critically associated with prognosis. The treatment starts with simple but vision saving steps and is continued with complicated surgical procedures later in the course of the disease. The goal of treatment is to restore the normal ocular surface anatomy and function. Limbal stem cell transplantation, amniotic membrane transplantation, and ultimately keratoprosthesis may be indicated depending on the patients' needs. PMID:25105018

[Eye-associated lymphoid tissue (EALT) is continuously spread throughout the ocular surface from the lacrimal gland to the lacrimal drainage system].

PubMed

Knop, E; Knop, N

2003-11-01

Components of the mucosal immune system (MALT) have been identified in the conjunctiva (as CALT) and the lacrimal drainage system (as LDALT). Their structural and functional relation with the established immune protection by the lacrimal gland is unclear. Macroscopically normal and complete tissues of the conjunctiva, lacrimal drainage system and lacrimal gland from human body donors were investigated by analysis of translucent whole mounts, and using histology, immunohistology as well as scanning and transmission electron microscopy. A typical diffuse lymphoid tissue, composed of effector cells of the immune system (T-lymphocytes and IgA producing plasma cells) under an epithelium that contains the IgA transporter SC, is not isolated in the conjunctiva and lacrimal drainage system. It is anatomically continuous from the lacrimal gland along its excretory ducts into the conjunctiva and from there via the lacrimal canaliculi into the lacrimal drainage system. Lymphoid follicles occur in a majority (about 60%) and with bilateral symmetry. The topography of CALT corresponds to the position of the cornea in the closed eye. These results show that the MALT of the lacrimal gland, conjunctiva and lacrimal drainage system constitute an anatomical and functional unit for immune protection of the ocular surface. Therefore it should be integrated as an "eye-associated lymphoid tissue" (EALT) into the MALT system of the body. EALT can detect ocular surface antigens by the lymphoid follicles and can supply other organs and the ocular surface including the lacrimal gland with specific effector cells via the regulated recirculation of lymphoid cells.

Intracellular trafficking of hyaluronic acid-chitosan oligomer-based nanoparticles in cultured human ocular surface cells.

PubMed

Contreras-Ruiz, Laura; de la Fuente, María; Párraga, Jenny E; López-García, Antonio; Fernández, Itziar; Seijo, Begoña; Sánchez, Alejandro; Calonge, Margarita; Diebold, Yolanda

2011-01-27

Nanoparticles are a promising alternative for ocular drug delivery, and our group has proposed that they are especially suited for ocular mucosal disorders. The goal of the present study was to determine which internalization pathway is used by cornea-derived and conjunctiva-derived cell lines to take up hyaluronic acid (HA)-chitosan oligomer (CSO)-based nanoparticles (HA-CSO NPs). We also determined if plasmids loaded onto the NPs reached the cell nucleus. HA-CSO NPs were made of fluoresceinamine labeled HA and CSO by ionotropic gelation and were conjugated with a model plasmid DNA for secreted alkaline phosphatase. Human epithelial cell lines derived from the conjunctiva and the cornea were exposed to HA-CSO NPs for 1 h and the uptake was investigated in living cells by fluorescence microscopy. The influence of temperature and metabolic inhibition, the effect of blocking hyaluronan receptors, and the inhibition of main endocytic pathways were studied by fluorometry. Additionally, the metabolic pathways implicated in the degradation of HA-CSO NPs were evaluated by lysosome identification. There was intracellular localization of plasmid-loaded HACSO NPs in both corneal and conjunctival cells. The intracellular presence of NPs diminished with time. HA-CSO NP uptake was significantly reduced by inhibition of active transport at 4 °C and by sodium azide. Uptake was also inhibited by blocking hyaluronan receptors with anti-CD44 Hermes-1 antibody, by excess HA, and by filipin, an inhibitor of caveolin-dependent endocytosis. HA-CSO NPs had no effect on cell viability. The transfection efficiency of the model plasmid was significantly higher in NP treated cells than in controls. HA-CSO NPs were internalized by two different ocular surface cell lines by an active transport mechanism. The uptake was mediated by hyaluronan receptors through a caveolin-dependent endocytic pathway, yielding remarkable transfection efficiency. Most of HA-CSO NPs were metabolized within 48 h. This uptake did not compromise cell viability. These findings further support the potential use of HA-CSO NPs to deliver genetic material to the ocular surface.

Comparison of Cornea Module and DermaInspect for noninvasive imaging of ocular surface pathologies

NASA Astrophysics Data System (ADS)

Steven, Philipp; Müller, Maya; Koop, Norbert; Rose, Christian; Hüttmann, Gereon

2009-11-01

Minimally invasive imaging of ocular surface pathologies aims at securing clinical diagnosis without actual tissue probing. For this matter, confocal microscopy (Cornea Module) is in daily use in ophthalmic practice. Multiphoton microscopy is a new optical technique that enables high-resolution imaging and functional analysis of living tissues based on tissue autofluorescence. This study was set up to compare the potential of a multiphoton microscope (DermaInspect) to the Cornea Module. Ocular surface pathologies such as pterygia, papillomae, and nevi were investigated in vivo using the Cornea Module and imaged immediately after excision by DermaInspect. Two excitation wavelengths, fluorescence lifetime imaging and second-harmonic generation (SHG), were used to discriminate different tissue structures. Images were compared with the histopathological assessment of the samples. At wavelengths of 730 nm, multiphoton microscopy exclusively revealed cellular structures. Collagen fibrils were specifically demonstrated by second-harmonic generation. Measurements of fluorescent lifetimes enabled the highly specific detection of goblet cells, erythrocytes, and nevus-cell clusters. At the settings used, DermaInspect reaches higher resolutions than the Cornea Module and obtains additional structural information. The parallel detection of multiphoton excited autofluorescence and confocal imaging could expand the possibilities of minimally invasive investigation of the ocular surface toward functional analysis at higher resolutions.

Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease.

PubMed

Wang, Y; Ogawa, Y; Dogru, M; Kawai, M; Tatematsu, Y; Uchino, M; Okada, N; Igarashi, A; Kujira, A; Fujishima, H; Okamoto, S; Shimazaki, J; Tsubota, K

2008-02-01

We investigated the effect of 0.05% topical cyclosporine (Cys) on the ocular surface and tear functions in dry eye patients with chronic GVHD (cGVHD) in a prospective comparative study. Thirty eyes of 15 patients refractory to baseline treatment were recruited and the patients assigned for topical Cys treatment group (14 eyes of 7 patients) and control group (12 eyes of 6 patients) respectively. Two patients dropped out because of intolerable irritation while using topical Cys eye drops. Visual analog scale symptom scores, corneal sensitivity, Schirmer I test value, tear film break-up time (TBUT), tear evaporation rate and ocular surface vital staining scores were recorded at baseline and at the end of the following one month. Conjunctival impression and brush cytology were performed before and after the treatment. After topical Cys treatment, significant improvements were found in symptom scores, corneal sensitivity, tear evaporation rate, TBUT, vital staining scores, goblet cells density, conjunctival squamous metaplasia grade, inflammatory cell numbers and the MUC5AC expression. Our study suggests that 0.05% topical Cys may be an effective treatment for dry eye patients with cGVHD. The improvements in the ocular surface and tear functions resulted presumably from the decreased inflammation, increased goblet cell density and MUC5AC mRNA expression. Bone Marrow Transplantation (2008) 41, 293-302; doi:10.1038/sj.bmt.1705900; published online 5 November 2007.

Therapeutic Effects of Sodium Hyaluronate on Ocular Surface Damage Induced by Benzalkonium Chloride Preserved Anti-glaucoma Medications

PubMed Central

Liu, Xing; Yu, Fen-Fen; Zhong, Yi-Min; Guo, Xin-Xing; Mao, Zhen

2015-01-01

Background: Long-term use of benzalkonium chloride (BAC)-preserved drugs is often associated with ocular surface toxicity. Ocular surface symptoms had a substantial impact on the glaucoma patients’ quality of life and compliance. This study aimed to investigate the effects of sodium hyaluronate (SH) on ocular surface toxicity induced by BAC-preserved anti-glaucoma medications treatment. Methods: Fifty-eight patients (101 eyes), who received topical BAC-preserved anti-glaucoma medications treatment and met the severe dry eye criteria, were included in the analysis. All patients were maintained the original topical anti-glaucoma treatment. In the SH-treated group (56 eyes), unpreserved 0.3% SH eye drops were administered with 3 times daily for 90 days. In the control group (55 eyes), phosphate-buffered saline were administered with 3 times daily for 90 days. Ocular Surface Disease Index (OSDI) questionnaire, break-up time (BUT) test, corneal fluorescein staining, corneal and conjunctival rose Bengal staining, Schirmer test, and conjunctiva impression cytology were performed sequentially on days 0 and 91. Results: Compared with the control group, SH-treated group showed decrease in OSDI scores (Kruskal-Wallis test: H = 38.668, P < 0.001), fluorescein and rose Bengal scores (Wilcoxon signed-ranks test: z = −3.843, P < 0.001, and z = −3.508, P < 0.001, respectively), increase in tear film BUT (t-test: t = −10.994, P < 0.001) and aqueous tear production (t-test: t = −10.328, P < 0.001) on day 91. The goblet cell density was increased (t-test: t = −9.981, P < 0.001), and the morphology of the conjunctival epithelium were also improved after SH treatment. Conclusions: SH significantly improved both symptoms and signs of ocular surface damage in patients with BAC-preserved anti-glaucoma medications treatment. SH could be proposed as a new attempt to reduce ocular surface toxicity, and alleviate symptoms of ocular surface damage in BAC-preserved anti-glaucoma medications treatment. PMID:26365960

Ocular manifestations of xeroderma pigmentosum: long term follow-up highlights the role of DNA repair in protection from sun damage

PubMed Central

Brooks, Brian P; Thompson, Amy H; Bishop, Rachel J; Clayton, Janine A; Chan, Chi-Chao; Tsilou, Ekaterini T; Zein, Wadih M; Tamura, Deborah; Khan, Sikandar G.; Ueda, Takahiro; Boyle, Jennifer; Oh, Kyu-Seon; Imoto, Kyoko; Inui, Hiroki; Moriwaki, Shin-Ichi; Emmert, Steffen; Iliff, Nicholas T.; Bradford, Porcia; DiGiovanna, John J.; Kraemer, Kenneth H

2013-01-01

Objective Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. Design Retrospective Observational Case Series Participants Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute for examination from 1964 to 2011. Eighty-three had XP, 3 had XP/Cockayne Syndrome complex, and 1 had XP/trichothiodystrophy complex. Methods Complete, age- and developmental stage-appropriate ophthalmic examination. Main Outcome Measures Visual acuity; eyelid, ocular surface and lens pathology; tear film and tear production measures; and cytological analysis of conjunctival surface swabs. Results Of the 87 patients, 91% had at least one ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement and 5% had no light perception in one or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than non-burning patients. Some patients also showed signs of limbal stem cell deficiency. Conclusions Our longitudinal study reports the ocular status of the largest group of XP patients systematically examined at one facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, as well as corneal abnormalities were present in this population. Burning and non-burning XP patients exhibit different rates of important ophthalmologic findings, including neoplasia. Additionally, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays major role in protection of the eye from sunlight induced damage. PMID:23601806

Antimicrobial role of human meibomian lipids at the ocular surface.

PubMed

Mudgil, Poonam

2014-10-14

Human meibomian lipids form the outermost lipid layer of the tear film and serve many important functions to maintain its integrity. Although not investigated earlier, these lipids may have antimicrobial properties that help in strengthening the innate host defense of tears at the ocular surface. The aim of this study was to investigate the antimicrobial role of human meibomian lipids. Ocular pathogenic bacteria, Staphylococcus aureus 31, Pseudomonas aeruginosa 19, Pseudomonas aeruginosa 20, and Serratia marcescens 35, were grown in the presence and absence of human meibomian lipids in an artificial tear solution at the physiological temperature. Viable counts were obtained to note the number of bacteria surviving the treatment with meibomian lipids. Bacterial cells were imaged using scanning electron microscopy to observe the damages caused by meibomian lipids. Viable count results showed that in the presence of meibomian lipids, growth of all bacteria was considerably lower. Scanning electron microscopy showed that meibomian lipids caused extensive cellular damage to bacteria as manifested in smaller size, loss of aggregation, abnormal phenotype, cellular distortion, damaged cell wall, and cell lysis. This is the first-ever report of the antimicrobial role of human meibomian lipids. These lipids possess antimicrobial properties against both Gram-positive and Gram-negative bacteria and are involved in the innate host defense of tears in protecting the ocular surface against microbial pathogens. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Requirement of Smad4 from Ocular Surface Ectoderm for Retinal Development.

PubMed

Li, Jing; Wang, Shusheng; Anderson, Chastain; Zhao, Fangkun; Qin, Yu; Wu, Di; Wu, Xinwei; Liu, Jia; He, Xuefei; Zhao, Jiangyue; Zhang, Jinsong

2016-01-01

Microphthalmia is characterized by abnormally small eyes and usually retinal dysplasia, accounting for up to 11% of the blindness in children. Right now there is no effective treatment for the disease, and the underlying mechanisms, especially how retinal dysplasia develops from microphthalmia and whether it depends on the signals from lens ectoderm are still unclear. Mutations in genes of the TGF-β superfamily have been noted in patients with microphthalmia. Using conditional knockout mice, here we address the question that whether ocular surface ectoderm-derived Smad4 modulates retinal development. We found that loss of Smad4 specifically on surface lens ectoderm leads to microphthalmia and dysplasia of retina. Retinal dysplasia in the knockout mice is caused by the delayed or failed differentiation and apoptosis of retinal cells. Microarray analyses revealed that members of Hedgehog and Wnt signaling pathways are affected in the knockout retinas, suggesting that ocular surface ectoderm-derived Smad4 can regulate Hedgehog and Wnt signaling in the retina. Our studies suggest that defective of ocular surface ectoderm may affect retinal development.

Requirement of Smad4 from Ocular Surface Ectoderm for Retinal Development

PubMed Central

Li, Jing; Wang, Shusheng; Anderson, Chastain; Zhao, Fangkun; Qin, Yu; Wu, Di; Wu, Xinwei; Liu, Jia; He, Xuefei; Zhao, Jiangyue; Zhang, Jinsong

2016-01-01

Microphthalmia is characterized by abnormally small eyes and usually retinal dysplasia, accounting for up to 11% of the blindness in children. Right now there is no effective treatment for the disease, and the underlying mechanisms, especially how retinal dysplasia develops from microphthalmia and whether it depends on the signals from lens ectoderm are still unclear. Mutations in genes of the TGF-β superfamily have been noted in patients with microphthalmia. Using conditional knockout mice, here we address the question that whether ocular surface ectoderm-derived Smad4 modulates retinal development. We found that loss of Smad4 specifically on surface lens ectoderm leads to microphthalmia and dysplasia of retina. Retinal dysplasia in the knockout mice is caused by the delayed or failed differentiation and apoptosis of retinal cells. Microarray analyses revealed that members of Hedgehog and Wnt signaling pathways are affected in the knockout retinas, suggesting that ocular surface ectoderm-derived Smad4 can regulate Hedgehog and Wnt signaling in the retina. Our studies suggest that defective of ocular surface ectoderm may affect retinal development. PMID:27494603

Functional anatomy and immunological interactions of ocular surface and adnexa.

PubMed

Paulsen, Friedrich

2008-01-01

This chapter gives an overview about the structures and physiology of the ocular surface and its adnexa and focuses in a second part on the possible meaning of eye-associated lymphoid tissue (EALT) in a context with the development of dry eye. Sections deal with (1) anatomy of the ocular surface, lacrimal gland, eyelid and nasolacrimal ducts. (2) The meaning and importance of the lacrimal functional unit and the function of the mucosal innate immune system are briefly summarized. (3) Finally, the occurrence and the possible function of EALT is discussed with regard to tolerance induction and dry eye. The epithelial surface of the eye and its specialized glandular infoldings produce the components of the tear film, which include water, protective antimicrobials, cytokines, lipids as well as mucins and trefoil factor family (TFF) peptides. Antimicrobials, mucins and TFF peptides perform a number of essential functions which, collectively, provide protection of the ocular surface. Their production changes in cases of dry eye. The development of EALT is a common feature frequently occurring in symptomatically normal conjunctiva and nasolacrimal ducts. The production of antimicrobials, mucins and TFF peptides can be linked with cell signaling, tear film rheology, and antimicrobial defense at the ocular surface. Changes in the production of such peptides and proteins in cases of dry eye support the assumption that these peptides and proteins are involved in the pathophysiological events that occur at the ocular surface and lacrimal apparatus. Whether special types of bacteria, viruses, or other factors, e.g., immune deviation, are responsible for the development of EALT in humans requires further investigation in prospective and experimental studies.

Mucins in contact lens wear and dry eye conditions.

PubMed

Ramamoorthy, Padmapriya; Nichols, Jason J

2008-08-01

Ocular mucins are thought to play integral roles in ocular surface lubrication, anchoring of the aqueous, stabilizing the lipid components of the tear film, eliminating foreign bodies and pathogens, and with potential involvement in cell cycle mediation and apoptotic activity of ocular surface epithelia. Ocular mucins are of secreted and membrane-associated types. Secreted mucins may be of large gel-forming type or small soluble mucins (e.g., MUC5AC and MUC7). Membrane-associated mucins such as MUCs 1 and 4 are a major component of the glycocalyx. They are thought to render structural support to the microplicae and mediate epithelial cell cycle and apoptotic activity. The alterations in ocular mucins with contact lens wear are unclear. Recent work shows mucin expression may be up-regulated during the early years of contact lens wear, and with long-term lens wear, mucin expression may return to normal levels or sub-normal levels, although this is not well understood. Further, the polar nature of mucins may be associated with their affinity for contact lens surfaces making them a component of contact lens deposition. This has potential implications in the wettability and tolerability of contact lenses, and may be impacted by surface coatings, polymer characteristics, or care solutions. Conjunctival mucin gene expression and secretion may be deficient in several ocular surface disorders associated with dry eye. Deficiency and alterations in glycosylation characteristics of MUC5AC and MUC2 have been reported in both Sjögren and non-Sjögren dry eye types. Decreased binding of the membrane-associated mucin MUC16 to the conjunctival epithelium has been reported in Sjögren dry eye while MUC1 alterations have been reported in Sjögren and non-Sjögren dry eye states. In view of the mucin involvement in dry eye conditions, stimulation of mucus secretion pathways may hold promise in the pharmaceutical treatment of dry eye.

Characterization of the corneal surface in limbal stem cell deficiency and after transplantation of cultured allogeneic limbal epithelial cells.

PubMed

Chen, Peng; Zhou, Qingjun; Wang, Junyi; Zhao, Xiaowen; Duan, Haoyun; Wang, Yao; Liu, Ting; Xie, Lixin

2016-09-01

The objective of this study was to characterize the changes that occur in the cornea during Limbal Stem Cell Deficiency (LSCD) and on the corneal surface after transplantation of ex vivo cultured allogeneic limbal epithelial transplantation (CALET). Forty-one pannus were analyzed to characterize the changes found in the cornea in LSCD. Nineteen impression cytology samples, including 14 pannus and five corneal buttons, obtained during subsequent procedures from patients who had undergone CALET were examined to assess the effect of CALET and to determine the long-term fate of donor cells. The presence of donor and recipient epithelial cells in each sample was determined by short tandem repeat (STR) amplification and fluorescent-multiplex polymerase chain reaction (PCR). Phenotypic analysis of the epithelium was performed by immunohistochemistry and real-time PCR. The expression of lineage markers was similar between pannus and conjunctivae, but not to corneas. Objective long-term benefits from the transplantation were recorded in most cases. After CALET, the lineage markers in the excised corneal buttons and pannus showed a limbus phenotype. DNA analysis of the 19 cases showed no donor cells present on the ocular surface beyond three months after CALET. LSCD was characterized by ingrowth of abnormal, inflamed tissue with a conjunctival phenotype. CALET was a useful technique for restoring the ocular surface in LSCD. However, such benefits did not necessarily correlate with survival of measurable numbers of donor cells on the ocular surface. The absence of donor DNA beyond three months raises questions regarding the period of ongoing immunosuppression and the origin of the regenerated corneal epithelium.

Randomised masked trial of the clinical safety and tolerability of MGO Manuka Honey eye cream for the management of blepharitis

PubMed Central

Craig, Jennifer P; Wang, Michael T M; Ganesalingam, Kalaivarny; Rupenthal, Ilva D; Swift, Simon; Loh, Chee Seang; Te Weehi, Leah; Cheung, Isabella M Y; Watters, Grant A

2017-01-01

Objective To assess the clinical safety and tolerability of a novel MGO Manuka Honey microemulsion (MHME) eye cream for the management of blepharitis in human subjects. Methods and analysis Twenty-five healthy subjects were enrolled in a prospective, randomised, paired-eye, investigator-masked trial. The MHME eye cream (Manuka Health New Zealand) was applied to the closed eyelids of one eye (randomised) overnight for 2 weeks. LogMAR visual acuity, eyelid irritation symptoms, ocular surface characteristics and tear film parameters were assessed at baseline, day 7 and day 14. Expression of markers of ocular surface inflammation (matrix metalloproteinase-9 and interleukin-6) and goblet cell function (MUC5AC) were quantified using impression cytology at baseline and day 14. Results There were no significant changes in visual acuity, eyelid irritation symptoms, ocular surface characteristics, tear film parameters and inflammatory marker expression during the 2-week treatment period in treated and control eyes (all p>0.05), and measurements did not differ significantly between eyes (all p>0.05). No major adverse events were reported. Two subjects experienced transient ocular stinging, presumably due to migration of the product into the eye, which resolved following aqueous irrigation. Conclusion The MHME eye cream application was found to be well tolerated in healthy human subjects and was not associated with changes in visual acuity, ocular surface characteristics, tear film parameters, expression of markers of inflammation or goblet cell function. The findings support future clinical efficacy trials in patients with blepharitis. Trial registration number ACTRN12616000540415 PMID:29354710

Detection of sialomucin complex (MUC4) in human ocular surface epithelium and tear fluid.

PubMed

Pflugfelder, S C; Liu, Z; Monroy, D; Li, D Q; Carvajal, M E; Price-Schiavi, S A; Idris, N; Solomon, A; Perez, A; Carraway, K L

2000-05-01

To evaluate human ocular surface epithelium and tear fluid for the presence of sialomucin complex (MUC4), a high-molecular-weight heterodimeric glycoprotein composed of mucin (ASGP-1) and transmembrane (ASGP-2) subunits. Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis assays were used to identify sialomucin complex RNA in ocular surface epithelia. Immunoprecipitation and immunoblot analysis were used to identify immunoreactive species in human tears and in the corneal and conjunctival epithelia using antibodies specific for carbohydrate and peptide epitopes on the sialomucin complex subunits. Immunofluorescence staining was used to detect sialomucin complex in frozen sections and impression cytology specimens of human cornea and conjunctival epithelia. ASGP-1- and ASGP-2-specific sequences were amplified from RNA extracted from both conjunctival and corneal epithelial biopsies by RT-PCR. Sialomucin complex transcripts were also detected in these tissues by Northern blot analysis, with a greater level of RNA detected in the peripheral than the central corneal epithelium. Sialomucin complex was immunoprecipitated from tear fluid samples and both corneal and conjunctival epithelia and detected by immunoblot analysis with specific anti-ASGP-1 and anti-ASGP-2 antibodies. The ASGP-1 peptide antibody HA-1 stained the full thickness of the corneal and conjunctival epithelia. In contrast, antibody 15H10, which reacts against a carbohydrate epitope on ASGP-1, stained only the superficial epithelial layers of these tissues. No staining was observed in the conjunctival goblet cells. Sialomucin complex was originally identified in rat mammary adenocarcinoma cells and has recently been shown to be produced by the ocular surface epithelia of rats. Furthermore, it has been identified as the rat homologue of human MUC4 mucin. The present studies show that it is expressed in the stratified epithelium covering the surface of the human eye and is present in human tear fluid. Expression of a carbohydrate-dependent epitope on the mucin subunit (ASGP-1) of sialomucin complex occurs in a differentiation-dependent fashion. Sialomucin complex joins MUC1 as another membrane mucin produced by the human ocular surface epithelia but is also found in the tear fluid, presumably in a soluble form, as found on the rat ocular surface.

Silk film biomaterials for ocular surface repair

NASA Astrophysics Data System (ADS)

Lawrence, Brian David

Current biomaterial approaches for repairing the cornea's ocular surface upon injury are partially effective due to inherent material limitations. As a result there is a need to expand the biomaterial options available for use in the eye, which in turn will help to expand new clinical innovations and technology development. The studies illustrated here are a collection of work to further characterize silk film biomaterials for use on the ocular surface. Silk films were produced from regenerated fibroin protein solution derived from the Bombyx mori silkworm cocoon. Methods of silk film processing and production were developed to produce consistent biomaterials for in vitro and in vivo evaluation. A wide range of experiments was undertaken that spanned from in vitro silk film material characterization to in vivo evaluation. It was found that a variety of silk film properties could be controlled through a water-annealing process. Silk films were then generated that could be use in vitro to produce stratified corneal epithelial cell sheets comparable to tissue grown on the clinical standard substrate of amniotic membrane. This understanding was translated to produce a silk film design that enhanced corneal healing in vivo on a rabbit injury model. Further work produced silk films with varying surface topographies that were used as a simplified analog to the corneal basement membrane surface in vitro. These studies demonstrated that silk film surface topography is capable of directing corneal epithelial cell attachment, growth, and migration response. Most notably epithelial tissue development was controllably directed by the presence of the silk surface topography through increasing cell sheet migration efficiency at the individual cellular level. Taken together, the presented findings represent a comprehensive characterization of silk film biomaterials for use in ocular surface reconstruction, and indicate their utility as a potential material choice in the development of innovative procedures and technologies for corneal repair.

Xenogeneic Acellular Conjunctiva Matrix as a Scaffold of Tissue-Engineered Corneal Epithelium

PubMed Central

Zhao, Haifeng; Qu, Mingli; Wang, Yao; Wang, Zhenyu; Shi, Weiyun

2014-01-01

Amniotic membrane-based tissue-engineered corneal epithelium has been widely used in the reconstruction of the ocular surface. However, it often degrades too early to ensure the success of the transplanted corneal epithelium when treating patients with severe ocular surface disorders. In the present study, we investigated the preparation of xenogeneic acellular conjunctiva matrix (aCM) and evaluated its efficacy and safety as a scaffold of tissue-engineered corneal epithelium. Native porcine conjunctiva was decellularized with 0.1% sodium dodecyl sulfate (SDS) for 12 h at 37°C and sterilized via γ-irradiation. Compared with native conjunctiva, more than 92% of the DNA was removed, and more than 90% of the extracellular matrix components (glycosaminoglycan and collagen) remained after the decellularization treatment. Compared with denuded amniotic membrane (dAM), the aCM possessed favorable optical transmittance, tensile strength, stability and biocompatibility as well as stronger resistance to degradation both in vitro and in vivo. The corneal epithelial cells seeded on aCM formed a multilayered epithelial structure and endured longer than did those on dAM. The aCM-based tissue-engineered corneal epithelium was more effective in the reconstruction of the ocular surface in rabbits with limbal stem cell deficiency. These findings support the application of xenogeneic acellular conjunctiva matrix as a scaffold for reconstructing the ocular surface. PMID:25375996

Ocular surface changes in thyroid eye disease.

PubMed

Ismailova, Dilyara S; Fedorov, Anatoly A; Grusha, Yaroslav O

2013-04-01

To study the incidence and risk factors of ocular surface damage in thyroid eye disease (TED) and to determine histological changes underlying positive vital staining in this condition. Forty-six patients (92 eyes) with TED were included in this study. Routine ophthalmologic examination, Schirmer test I, vital staining and corneal sensitivity were performed. Fifteen patients with positive vital staining underwent impression cytology and incisional biopsy. Positive vital staining with lissamine green was observed in 56 eyes (60.9%), 30 patients (65.2%). The average degree of staining was 4.57 ± 0.44 (National Eye Institute Workshop grading system). Severe dry eye syndrome was found in 16%. The following histological changes of conjunctiva were revealed: significant epithelial dystrophy with cell polymorphism, goblet cells loss, excessive desquamation and epithelial keratinization with local leukocytic infiltration of substantia propria. According to our results dry eye syndrome is present in 65.2% of patients (60.9% eyes) with TED. Significant risk factors of ocular surface damage in TED were exophthalmos, lagophthalmos, palpebral fissure height and lower lid retraction. Positive conjunctival staining results from punctuate epithelial erosions and excessive desquamation of superficial cells. Histopathologic changes detected in conjunctiva consistent with dry eye and are not specific for TED.

Limitations of an ocular surface inflammatory biomarker in impression cytology specimens.

PubMed

Yafawi, Rolla; Ko, Mira; Sace, Frederick P; John-Baptiste, Annette

2013-03-01

A number of ocular conditions, such as dry eye, are associated with inflammation on the surface of the eye leading to irritation and ocular pain. Many drugs such as chemotherapeutics, beta blockers, angiotensin-converting enzymes and so forth also cause dry eye but currently there are no validated ocular surface biomarkers available. We evaluated sample stability, assay sensitivity, reproducibility and overall performance of impression cytology (IC) utilizing the cellular surface biomarker human leukocyte antigen DR-1 (HLA-DR) as an ocular surface inflammatory biomarker by flow cytometry in a fit-for-purpose validation study. Additionally, subjects classified as normal or having various degrees of dry eye were evaluated to determine if HLA-DR could demonstrate a clear separation between normal and dry eye samples. The assay demonstrated high dynamic range detecting a broad range of fluorescent intensities in healthy donors. Additionally, inter, intra and stability assay results demonstrated strong concordance and low variability. Overall CV% for both assays were less than 25% for all measured parameters. However, high variability was observed for donor samples assayed beyond day 10 post IC sample collection (4.2-110.8 CV%). HLA-DR expression demonstrated a progressive increase in patients with mild to severe levels of dry eye disease providing sufficient evidence it is sensitive enough to monitor inflammatory effects of dry eye when coupled with additional biomarkers and/or methodologies such as cytokine analysis or ICAM-1. This biomarker can be used to monitor ocular surface disorders in patients and to evaluate potential treatment options during drug development. Although our results demonstrate this methodology is reproducible for routine evaluation, limitations around sample integrity exist. The ocular cell surface inflammatory biomarker, HLA-DR coupled with impression cytology is a simple non-invasive robust, specific and reproducible assay that can be utilized to measure inflammatory infiltrates on the surface of the eye in IC samples less than 10-days old.

Autophagy mediates cell cycle response by regulating nucleocytoplasmic transport of PAX6 in limbal stem cells under ultraviolet-A stress

PubMed Central

Laggner, Maria; Pollreisz, Andreas; Schmidinger, Gerald; Schmidt-Erfurth, Ursula; Chen, Ying-Ting

2017-01-01

Limbal stem cells (LSC) account for homeostasis and regeneration of corneal epithelium. Solar ultraviolet A (UVA) is the major source causing oxidative damage in the ocular surface. Autophagy, a lysosomal degradation mechanism, is essential for physiologic function and stress defense of stem cells. PAX6, a master transcription factor governing corneal homeostasis by regulating cell cycle and cell fate of LSC, responds to oxidative stress by nucleocytoplasmic shuttling. Impaired autophagy and deregulated PAX6 have been reported in oxidative stress-related ocular surface disorders. We hypothesize a functional role for autophagy and PAX6 in LSC’s stress response to UVA. Therefore, human LSC colonies were irradiated with a sub-lethal dose of UVA and autophagic activity and intracellular reactive oxygen species (ROS) were measured by CYTO-ID assay and CM-H2DCFDA live staining, respectively. Following UVA irradiation, the percentage of autophagic cells significantly increased in LSC colonies while intracellular ROS levels remained unaffected. siRNA-mediated knockdown (KD) of ATG7 abolished UVA-induced autophagy and led to an excessive accumulation of ROS. Upon UVA exposure, LSCs displayed nuclear-to-cytoplasmic translocation of PAX6, while ATG7KD or antioxidant pretreatment largely attenuated the intracellular trafficking event. Immunofluorescence showing downregulation of proliferative marker PCNA and induction of cell cycle regulator p21 indicates cell cycle arrest in UVA-irradiated LSC. Abolishing autophagy, adenoviral-assisted restoration of nuclear PAX6 or antioxidant pretreatment abrogated the UVA-induced cell cycle arrest. Adenoviral expression of an ectopic PAX gene, PAX7, did not affect UVA cell cycle response. Furthermore, knocking down PAX6 attenuated the cell cycle progression of irradiated ATG7KD LSC by de-repressing p21 expression. Collectively, our data suggest a crosstalk between autophagy and PAX6 in regulating cell cycle response of ocular progenitors under UVA stress. Autophagy deficiency leads to impaired intracellular trafficking of PAX6, perturbed redox balance and uncurbed cell cycle progression in UVA-stressed LSCs. The coupling of autophagic machinery and PAX6 in cell cycle regulation represents an attractive therapeutic target for hyperproliferative ocular surface disorders associated with solar radiation. PMID:28700649

The role of the lacrimal functional unit in the pathophysiology of dry eye.

PubMed

Stern, Michael E; Gao, Jianping; Siemasko, Karyn F; Beuerman, Roger W; Pflugfelder, Stephen C

2004-03-01

The majority of dry eye symptoms are due to a chronic inflammation of the lacrimal functional unit resulting in a loss of tear film integrity and normal function. This leads to a reduction in the ability of the ocular surface to respond to environmental challenges. The underlying cause of tear film dysfunction is the alteration of tear aqueous, mucin, and lipid components. This may result from a systemic autoimmune disease or a local autoimmune event. A lack of systemic androgen support to the lacrimal gland has been shown to be a facilitative factor in the initiation of this type of pathophysiology. Tear secretion is controlled by the lacrimal functional unit consisting of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland and the interconnecting innervation. If any portion of this functional unit is compromised, lacrimal gland support to the ocular surface is impeded. Factors such as neurogenic inflammation and T cell involvement in the disease pathogenesis as well as newly developed animal models of ocular surface inflammation are discussed.

Effects of DA-6034, a flavonoid derivative, on mucin-like glycoprotein and ocular surface integrity in a rabbit model.

PubMed

Choi, Seul Min; Seo, Mi Jeong; Lee, Yeong Geon; Lee, Min Jung; Jeon, Hyung Jun; Kang, Kyung Koo; Ahn, Byoung Ok; Yoo, Moohi

2009-01-01

This study was designed to assess whether DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone monohydrate), a new synthetic derivative of eupatilin, increases secretion of mucin-like glycoprotein and some mucins species in conjunctiva and cornea, and contributes to the preservation of ocular surface integrity. Human conjunctival and corneal epithelial cells were incubated with DA-6034 (1-250 microM). To investigate mucin secreting activity more directly, isolated rat conjunctival goblet cells were also used. Corneal protection was investigated using a desiccation-induced rabbit model of dry eye syndrome. It was found that DA-6034 increased mucin-like glycoprotein levels of both conjunctival and corneal epithelial cells at concentrations above 100 microM. Using human conjunctival epithelial cells, it was demonstrated that treatment with DA-6034 (200 microM) significantly increased production of some mucins species including MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC16. DA-6034 also significantly increased MUC5AC production from conjunctival goblet cells isolated from rats. In the rabbit desiccation model, an ophthalmic suspension containing 3% DA-6034 significantly reduced corneal damage induced by desiccation. These results suggest that DA-6034 is a good candidate for treatment of dry eye through maintaining ocular surface integrity, which might be related to mucin secretion.

Effect of intermittent shear stress on corneal epithelial cells using an in vitro flow culture model.

PubMed

Hampel, Ulrike; Garreis, Fabian; Burgemeister, Fabian; Eßel, Nicole; Paulsen, Friedrich

2018-04-27

The aim of this study was to establish and to evaluate an in vitro model for culturing human telomerase-immortalized corneal epithelial (hTCEpi) cells under adjustable medium flow mimicking the movements of the tear film on the ocular surface. Using an IBIDI pump system, cells were cultured under unidirectional, continuous or oscillating, discontinuous medium flow. Cell surface and cytoskeletal architecture were investigated by scanning electron microscopy and immunofluorescence. Gene expression of e-cadherin, occludin, tight junction protein (TJP), desmoplakin, desmocollin and mucins was investigated by real-time PCR. Protein expression of desmoplakin, TJP, occludin and e-cadherin was analyzed by western blot and localization was detected by immunofluorescence. Rose bengal staining was used to assess mucin (MUC) barrier integrity. MUC1, -4 and -16 proteins were localized by immunofluorescence. Medium flow-induced shear stress dramatically changed cellular morphology of hTCEpi. Cells subjected to discontinuous shear stress displayed the typical flattened, polygonal cell shape of the superficial layer of stratified squamous epithelia. Cell surfaces showed less bulging under shear stress and less extracellular gaps. The mRNA expression of E-cadherin, occludin and TJP were increased under oscillatory medium flow. Desmoplakin and occludin protein were upregulated under oscillatory shear stress. Stress fiber formation was not aligned to flow direction. MUC1, -4, and -16 protein were localized under all culture conditions, a regulation on mRNA expression was not detectable. Rose Bengal uptake was diminished under unidirectional conditions. Our findings suggest that shear stress as it occurs at the ocular surface during blinking exerts marked effects on corneal epithelial cells, such as changes in cellular morphology and expression of cell junctions. The described model may be useful for in vitro investigations of ocular surface epithelia as it represents a much more physiologic reproduction of the in vivo situation than the commonly applied static culture conditions. Copyright © 2018. Published by Elsevier Inc.

Neural Regulation of Lacrimal Gland Secretory Processes: Relevance in Dry Eye Diseases

PubMed Central

Dartt, Darlene A.

2013-01-01

The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions. PMID:19376264

Ocular chemical injuries and their management.

PubMed

Singh, Parul; Tyagi, Manoj; Kumar, Yogesh; Gupta, K K; Sharma, P D

2013-05-01

Chemical burns represent potentially blinding ocular injuries and constitute a true ocular emergency requiring immediate assessment and initiation of treatment. The majority of victims are young and exposure occurs at home, work place and in association with criminal assaults. Alkali injuries occur more frequently than acid injuries. Chemical injuries of the eye produce extensive damage to the ocular surface epithelium, cornea, anterior segment and limbal stem cells resulting in permanent unilateral or bilateral visual impairment. Emergency management if appropriate may be single most important factor in determining visual outcome. This article reviews the emergency management and newer techniques to improve the prognosis of patients with chemical injuries.

Topical administration of interleukin-1 receptor antagonist as a therapy for aqueous-deficient dry eye in autoimmune disease.

PubMed

Vijmasi, Trinka; Chen, Feeling Y T; Chen, Ying Ting; Gallup, Marianne; McNamara, Nancy

2013-01-01

Dry eye is commonly associated with autoimmune diseases such as Sjögren's syndrome (SS), in which exocrinopathy of the lacrimal gland leads to aqueous tear deficiency and keratoconjunctivitis sicca (KCS). KCS is among the most common and debilitating clinical manifestations of SS that is often recalcitrant to therapy. We established mice deficient in the autoimmune regulator (Aire) gene as a model for autoimmune-mediated aqueous-deficient dry eye. In Aire-deficient mice, CD4+ T cells represent the main effector cells and local signaling via the interleukin-1 (IL-1/IL-1R1) pathway provides an essential link between autoreactive CD4+ T cells and ocular surface disease. In the current study, we evaluated the efficacy of topical administration of IL-1R1 antagonist (IL-1RA) anakinra in alleviating ocular surface damage resulting from aqueous-deficient dry eye in the setting of autoimmune disease. We compared the effect of commercially available IL-1R1 antagonist, anakinra (50 μg/mL concentration) to that of carboxymethylcellulose (CMC) vehicle control as a treatment for dry eye. Age-matched, Aire-deficient mice were treated three times daily with anakinra or CMC vehicle for 14 days using side-by-side (n = 4 mice/group) and paired-eye (n = 5) comparisons. We assessed (1) ocular surface damage with lissamine green staining; (2) tear secretion with wetting of phenol-red threads; (3) goblet cell (GC) mucin glycosylation with lectin histochemistry; (4) immune cell infiltration using anti-F4/80, CD11c, and CD4 T cell antibodies; and (5) gene expression of cornified envelope protein, Small Proline-Rich Protein-1B (SPRR1B) with real-time quantitative polymerase chain reaction. Aire-deficient mice treated with anakinra experienced significant improvements in ocular surface integrity and tear secretion. After 7 days of treatment, lissamine green staining decreased in eyes treated with anakinra compared to an equivalent increase in staining following treatment with CMC vehicle alone. By day 14, lissamine green staining in anakinra-treated eyes remained stable while eyes treated with CMC vehicle continued to worsen. Accordingly, there was a progressive decline in tear secretion in eyes treated with the CMC vehicle compared to a progressive increase in the anakinra-treated eyes over the 2-week treatment period. Aberrant acidification of GC mucins and pathological keratinization of the ocular surface were significantly reduced in anakinra-treated eyes. Significantly fewer Maackia amurensis leukoagglutinin positive goblet cells were noted in the conjunctiva of anakinra-treated eyes with a corresponding decrease in the expression of the pathological keratinization marker, SPRR1B. Finally, there was a downward trend in the infiltration of each immune cell type following anakinra treatment, but the cell counts compared to eyes treated with the vehicle alone were not significantly different. IL-1R antagonist, anakinra, demonstrates therapeutic benefits as a topical treatment for aqueous-deficient dry eye in a spontaneous mouse model of autoimmune KCS that mimics the clinical characteristics of SS. Targeting the IL-1/IL-1R1 signaling pathway through topical administration of IL-1RA may provide a novel option to improve ocular surface integrity, increase tear secretion, and restore the normal glycosylation pattern of GC mucins in patients with SS.

Topical administration of interleukin-1 receptor antagonist as a therapy for aqueous-deficient dry eye in autoimmune disease

PubMed Central

Vijmasi, Trinka; Chen, Feeling YT; Chen, Ying Ting; Gallup, Marianne

2013-01-01

Purpose Dry eye is commonly associated with autoimmune diseases such as Sjögren’s syndrome (SS), in which exocrinopathy of the lacrimal gland leads to aqueous tear deficiency and keratoconjunctivitis sicca (KCS). KCS is among the most common and debilitating clinical manifestations of SS that is often recalcitrant to therapy. We established mice deficient in the autoimmune regulator (Aire) gene as a model for autoimmune-mediated aqueous-deficient dry eye. In Aire-deficient mice, CD4+ T cells represent the main effector cells and local signaling via the interleukin-1 (IL-1/IL-1R1) pathway provides an essential link between autoreactive CD4+ T cells and ocular surface disease. In the current study, we evaluated the efficacy of topical administration of IL-1R1 antagonist (IL-1RA) anakinra in alleviating ocular surface damage resulting from aqueous-deficient dry eye in the setting of autoimmune disease. Methods We compared the effect of commercially available IL-1R1 antagonist, anakinra (50 μg/mL concentration) to that of carboxymethylcellulose (CMC) vehicle control as a treatment for dry eye. Age-matched, Aire-deficient mice were treated three times daily with anakinra or CMC vehicle for 14 days using side-by-side (n=4 mice/group) and paired-eye (n=5) comparisons. We assessed (1) ocular surface damage with lissamine green staining; (2) tear secretion with wetting of phenol-red threads; (3) goblet cell (GC) mucin glycosylation with lectin histochemistry; (4) immune cell infiltration using anti-F4/80, CD11c, and CD4 T cell antibodies; and (5) gene expression of cornified envelope protein, Small Proline-Rich Protein-1B (SPRR1B) with real-time quantitative polymerase chain reaction. Results Aire-deficient mice treated with anakinra experienced significant improvements in ocular surface integrity and tear secretion. After 7 days of treatment, lissamine green staining decreased in eyes treated with anakinra compared to an equivalent increase in staining following treatment with CMC vehicle alone. By day 14, lissamine green staining in anakinra-treated eyes remained stable while eyes treated with CMC vehicle continued to worsen. Accordingly, there was a progressive decline in tear secretion in eyes treated with the CMC vehicle compared to a progressive increase in the anakinra-treated eyes over the 2-week treatment period. Aberrant acidification of GC mucins and pathological keratinization of the ocular surface were significantly reduced in anakinra-treated eyes. Significantly fewer Maackia amurensis leukoagglutinin positive goblet cells were noted in the conjunctiva of anakinra-treated eyes with a corresponding decrease in the expression of the pathological keratinization marker, SPRR1B. Finally, there was a downward trend in the infiltration of each immune cell type following anakinra treatment, but the cell counts compared to eyes treated with the vehicle alone were not significantly different. Conclusions IL-1R antagonist, anakinra, demonstrates therapeutic benefits as a topical treatment for aqueous-deficient dry eye in a spontaneous mouse model of autoimmune KCS that mimics the clinical characteristics of SS. Targeting the IL-1/IL-1R1 signaling pathway through topical administration of IL-1RA may provide a novel option to improve ocular surface integrity, increase tear secretion, and restore the normal glycosylation pattern of GC mucins in patients with SS. PMID:24068863

Transcription, Translation, and Function of Lubricin, a Boundary Lubricant, at the Ocular Surface

PubMed Central

Schmidt, Tannin A.; Sullivan, David A.; Knop, Erich; Richards, Stephen M.; Knop, Nadja; Liu, Shaohui; Sahin, Afsun; Darabad, Raheleh Rahimi; Morrison, Sheila; Kam, Wendy R.; Sullivan, Benjamin D.

2013-01-01

Importance Lubricin may be an important barrier to the development of corneal and conjunctival epitheliopathies that may occur in dry eye disease and contact lens wear. Objective To test the hypotheses that lubricin (ie, proteoglycan 4 [PRG4]), a boundary lubricant, is produced by ocular surface epithelia and acts to protect the cornea and conjunctiva against significant shear forces generated during an eyelid blink and that lubricin deficiency increases shear stress on the ocular surface and promotes corneal damage. Design, Setting, and Participants Human, porcine, and mouse tissues and cells were processed for molecular biological, immunohistochemical, and tribological studies, and wild-type and PRG4 knockout mice were evaluated for corneal damage. Results Our findings demonstrate that lubricin is transcribed and translated by corneal and conjunctival epithelial cells. Lubricin messenger RNA is also present in lacrimal and meibomian glands, as well as in a number of other tissues. Absence of lubricin in PRG4 knockout mice is associated with a significant increase in corneal fluorescein staining. Our studies also show that lubricin functions as an effective friction-lowering boundary lubricant at the human cornea-eyelid interface. This effect is specific and cannot be duplicated by the use of hyaluronate or bovine serum albumin solutions. Conclusions and Relevance Our results show that lubricin is transcribed, translated, and expressed by ocular surface epithelia. Moreover, our findings demonstrate that lubricin presence significantly reduces friction between the cornea and conjunctiva and that lubricin deficiency may play a role in promoting corneal damage. PMID:23599181

Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface.

PubMed

Schmidt, Tannin A; Sullivan, David A; Knop, Erich; Richards, Stephen M; Knop, Nadja; Liu, Shaohui; Sahin, Afsun; Darabad, Raheleh Rahimi; Morrison, Sheila; Kam, Wendy R; Sullivan, Benjamin D

2013-06-01

Lubricin may be an important barrier to the development of corneal and conjunctival epitheliopathies that may occur in dry eye disease and contact lens wear. To test the hypotheses that lubricin (ie, proteoglycan 4 [PRG4 ]), a boundary lubricant, is produced by ocular surface epithelia and acts to protect the cornea and conjunctiva against significant shear forces generated during an eyelid blink and that lubricin deficiency increases shear stress on the ocular surface and promotes corneal damage. Human, porcine, and mouse tissues and cells were processed for molecular biological, immunohistochemical, and tribological studies, and wild-type and PRG4 knockout mice were evaluated for corneal damage. Our findings demonstrate that lubricin is transcribed and translated by corneal and conjunctival epithelial cells. Lubricin messenger RNA is also present in lacrimal and meibomian glands, as well as in a number of other tissues. Absence of lubricin in PRG4 knockout mice is associated with a significant increase in corneal fluorescein staining. Our studies also show that lubricin functions as an effective friction-lowering boundary lubricant at the human cornea-eyelid interface. This effect is specific and cannot be duplicated by the use of hyaluronate or bovine serum albumin solutions. Our results show that lubricin is transcribed, translated, and expressed by ocular surface epithelia. Moreover, our findings demonstrate that lubricin presence significantly reduces friction between the cornea and conjunctiva and that lubricin deficiency may play a role in promoting corneal damage.

Apoptosis of conjunctival epithelial cells before and after the application of autologous serum eye drops in severe dry eye disease.

PubMed

Rybickova, Ivana; Vesela, Viera; Fales, Ivan; Skalicka, Pavlina; Jirsova, Katerina

2016-06-01

To assess the impact of autologous serum eye drops on the level of ocular surface apoptosis in patients with bilateral severe dry eye disease. This prospective study was conducted on 10 patients with severe dry eye due to graft versus host disease (group 1) and 6 patients with severe dry eye due to primary Sjögren's syndrome (group 2). Impression cytology specimens from the bulbar conjunctiva were obtained before and after a three-month treatment with 20% autologous serum eye drops applied a maximum of 12 times a day together with regular therapy with artificial tears. The percentage of apoptotic epithelial cells was evaluated immunochemically using anti-active caspase 3 antibody. In group 1, the mean percentage of apoptotic cells was 3.6% before the treatment. The three-month treatment led to a significant decrease to a mean percentage of 1.8% (P = 0.028). The mean percentage of apoptotic conjunctival cells decreased from 5.4% before the treatment to 3.8% in group 2; however, these results did not reach the level of significance. Three-month autologous serum treatment led to the improvement of ocular surface apoptosis, especially in the group of patients with severe dry eye due to graft versus host disease. This result supports the very positive effect of autologous serum on the ocular surface in patients suffering from severe dry eye.

Altered Mucin and Glycoprotein Expression in Dry Eye Disease.

PubMed

Stephens, Denise N; McNamara, Nancy A

2015-09-01

Mucins are among the many important constituents of a healthy tear film. Mucins secreted and/or associated with conjunctival goblet cells, ocular mucosal epithelial cells, and the lacrimal gland must work together to create a stable tear film. Although many studies have explored the mechanism(s) whereby mucins maintain and protect the ocular surface, the effects of dry eye on the structure and function of ocular mucins are unclear. Here, we summarize current findings regarding ocular mucins and how they are altered in dry eye. We performed a literature review of studies exploring the expression of mucins produced and/or associated with tissues that comprise the lacrimal functional unit and how they are altered in dry eye. We also summarize new insights on the immune-mediated effects of aqueous tear deficiency on ocular surface mucins that we discovered using a mouse model of dry eye. Although consistent decreases in MUC5AC and altered expression of membrane-bound mucins have been noted in both Sjögren and non-Sjögren dry eye, many reports of altered mucins in dry eye are contradictory. Mechanistic studies, including our own, suggest that changes in the glycosylation of mucins rather than the proteins themselves may occur as the direct result of local inflammation induced by proinflammatory mediators, such as interleukin-1. Altered expression of ocular mucins in dry eye varies considerably from study to study, likely attributed to inherent difficulties in analyzing small-volume tear samples, as well as differences in tear collection methods and disease severity in dry eye cohorts. To better define the functional role of ocular mucin glycosylation in the pathogenesis of dry eye disease, we propose genomic and proteomic studies along with biological pathway analysis to reveal novel avenues for exploration.

Changes in the tear film and ocular surface from dry eye syndrome.

PubMed

Johnson, Michael E; Murphy, Paul J

2004-07-01

Dry eye syndrome (DES) refers to a spectrum of ocular surface diseases with diverse and frequently multiple aetiologies. The common feature of the various manifestations of DES is an abnormal tear film. Tear film abnormalities associated with DES are tear deficiency, owing to insufficient supply or excessive loss, and anomalous tear composition. These categorizations are artificial, as in reality both often coexist. DES disrupts the homeostasis of the tear film with its adjacent structures, and adversely affects its ability to perform essential functions such as supporting the ocular surface epithelium and preventing microbial invasion. In addition, whatever the initial trigger, moderate and severe DES is characterized by ocular surface inflammation, which in turn becomes the cause and consequence of cell damage, creating a self-perpetuating cycle of deterioration. Progress has been made in our understanding of the aetiology and pathogenesis of DES, and these advances have encouraged a proliferation of therapeutic options. This article aims to amalgamate prevailing ideas of DES development, and to assist in that, relevant aspects of the structure, function, and production of the tear film are reviewed. Additionally, a synopsis of therapeutic strategies for DES is presented, detailing treatments currently available, and those in development.

The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice.

PubMed

Ohguchi, Takeshi; Kojima, Takashi; Ibrahim, Osama M; Nagata, Taeko; Shimizu, Takahiko; Shirasawa, Takuji; Kawakita, Tetsuya; Satake, Yoshiyuki; Tsubota, Kazuo; Shimazaki, Jun; Ishida, Susumu

2013-11-21

To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1(-/-)) mice. Two percent Rebamipide ophthalmic solution was applied to 40-week-old male Sod1(-/-) and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), in the conjunctiva to compare the results before and after rebamipide instillations. The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1(-/-) than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1(-/-) mice. The mean IL-6, IL-17, TNF-α, and IFN-γ levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout.

Expression of Lipid Peroxidation Markers in the Tear Film and Ocular Surface of Patients with Non-Sjogren Syndrome: Potential Biomarkers for Dry Eye Disease.

PubMed

Choi, Won; Lian, Cui; Ying, Li; Kim, Ga Eon; You, In Cheon; Park, Soo Hyun; Yoon, Kyung Chul

2016-09-01

To investigate the expression of lipid peroxidation markers in the tear film and ocular surface and their correlation with disease severity in patients with dry eye disease. The concentrations of hexanoyl-lysine (HEL), 4-hydroxy-2-nonenal (HNE), and malondialdehyde (MDA) were measured with enzyme-linked immunosorbent assays in tears obtained from 44 patients with non-Sjogren syndrome dry eye and 33 control subjects. The correlations between the marker levels and the tear film and ocular surface parameters, including tear film break-up time (BUT), Schirmer tear value, tear clearance rate, keratoepitheliopathy scores, corneal sensitivity, conjunctival goblet cell density, and symptom score, were analyzed. The expression of the lipid peroxidation markers HEL, 4-HNE, and MDA in the conjunctiva was evaluated using immunohistochemistry. The concentrations of HEL, 4-HNE, and MDA were 279.84 ± 69.98 nmol/L, 0.02 ± 0.01 μg/mL, and 3.80 ± 1.05 pmol/mg in control subjects and 283.21 ± 89.67 nmol/L (p = 0.97), 0.20 ± 0.03 μg/mL (p < 0.01), and 13.32 ± 4.03 pmol/mg (p < 0.01) in dry eye patients. 4-HNE and MDA levels significantly correlated with BUT, Schirmer tear value, tear clearance rate, keratoepitheliopathy scores, conjunctival goblet cell density, and symptom score (p < 0.05), whereas HEL levels did not correlate with these parameters. Staining intensities for 4-HNE and MDA increased in dry eye patients. The expression of late lipid peroxidation markers, 4-HNE and MDA, increases in the tear film and ocular surface of patients with dry eye. The levels correlate with various tear film and ocular surface parameters and may reflect the severity of dry eye disease.

Corneal Expression of SLURP-1 by Age, Sex, Genetic Strain, and Ocular Surface Health

PubMed Central

Swamynathan, Sudha; Delp, Emili E.; Harvey, Stephen A. K.; Loughner, Chelsea L.; Raju, Leela; Swamynathan, Shivalingappa K.

2015-01-01

Purpose Although secreted Ly6/urokinase-type plasminogen activator receptor–related protein-1 (Slurp1) transcript is highly abundant in the mouse cornea, corresponding protein expression remains uncharacterized. Also, SLURP1 was undetected in previous tear proteomics studies, resulting in ambiguity about its baseline levels. Here, we examine mouse corneal Slurp1 expression in different sexes, age groups, strains, and health conditions, and quantify SLURP1 in human tears from healthy or inflamed ocular surfaces. Methods Expression of Slurp1 in embryonic day-13 (E13), E16, postnatal day-1 (PN1), PN10, PN20, and PN70 Balb/C, FVBN, C57Bl/6, and DBA/2J mouse corneas, Klf4Δ/ΔCE corneas with corneal epithelial–specific ablation of Klf4, migrating cells in wild-type corneal epithelial wound edge, and in corneas exposed to pathogen-associated molecular patterns (PAMPs) poly(I:C), zymosan-A, or Pam3Csk4 was examined by QPCR, immunoblots, and immunofluorescent staining. Human SLURP1 levels were quantified by ELISA in tears from 34 men and women aged 18 to 80 years. Results Expression of Slurp1, comparable in different strains and sexes, was low in E13, E16, PN1, and PN10 mouse corneas, and increased rapidly after eyelid opening in a Klf4-dependent manner. We found Slurp1 was downregulated in corneas exposed to PAMPs, and in migrating cells at the wound edge. Human SLURP1 expression, comparable in different sexes and age groups, was significantly decreased in tears from inflamed ocular surfaces (0.34%) than those from healthy individuals (0.77%). Conclusions These data describe the influence of age, sex, genetic background, and ocular surface health on mouse corneal expression of Slurp1, establish the baseline for human tear SLURP1 expression, and identify SLURP1 as a useful diagnostic and/or therapeutic target for inflammatory ocular surface disorders. PMID:26670825

Evaluation of lipid oxidative stress status and inflammation in atopic ocular surface disease

PubMed Central

Wakamatsu, Tais H.; Ayako, Igarashi; Takano, Yoji; Matsumoto, Yukihiro; Ibrahim, Osama M.A.; Okada, Naoko; Satake, Yoshiyuki; Fukagawa, Kazumi; Shimazaki, Jun; Tsubota, Kazuo; Fujishima, Hiroshi

2010-01-01

Background Although the oxidative stress status in atopic skin disease has been reported to be elevated, there are still no studies related to the status of oxidative stress in atopic ocular surface disease. The purpose of this study was to evaluate the ocular surface lipid oxidative stress status and inflammation in atopic keratoconjunctivitis (AKC) patients and normal subjects. Methods Twenty eight eyes of 14 patients (9 males, 5 females) with AKC and 18 eyes of 9 age and sex matched (4 males and 5 females) normal healthy controls were examined in this prospective study. The severity of atopic dermatitis (AD) was scored by the SCORing Atopic Dermatitis (SCORAD) index. All subjects underwent Schirmer test, tear film break up time (BUT), fluorescein/Rose Bengal stainings, tear collection, and brush cytology from the upper palpebral conjunctiva. The brush cytology samples were stained with Diff-Quik for differentiation of inflammatory cells and immunohistochemistry (IHC) staining with HEL (hexanoyl-lysine) and 4-HNE (4-hydroxy-2-nonenal) to study lipid oxidation. HEL and cytokine (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ)) levels were measured by enzyme-linked immunosorbent assay (ELISA) from tear samples of AKC patients and control subjects. Toluidine Blue and IHC staining with HEL, 4-HNE and cluster of differentiation 45 (CD45) were performed on papillary samples of AKC patients. This study was conducted in compliance with the “Declaration of Helsinki.” Results The tear stability and vital staining scores were significantly worse in eyes of AKC patients (p<0.05) compared to the controls. Inflammatory cells and positively stained conjunctival epithelial cells for HEL and 4-HNE showed a significant elevation in brush cytology samples of AKC patients. Significantly higher levels of HEL and cytokines were detected in tears of AKC patients compared to controls. Papillary specimens also revealed many CD45 inflammatory cells as well as many cells positively stained with HEL and 4-HNE in IHC. A strong significant linear positive correlation between conjunctival inflammation and epithelial lipid oxidative stress status was observed. Conjunctival lipid oxidative stress also correlated strongly with tear HEL levels and epithelial damage scores. Conclusions The ocular surface disease in AKC was characterized by marked tear instability, ocular surface epithelial damage, increase in inflammatory infiltrates and presence of increased lipid oxidation. PMID:21139696

Severe Phenotype of Keratitis-Ichthyosis-Deafness Syndrome With Presumed Ocular Surface Squamous Neoplasia.

PubMed

Serrano-Ahumada, Ana Silvia; Cortes-González, Vianney; González-Huerta, Luz María; Cuevas, Sergio; Aguilar-Lozano, Luis; Villanueva-Mendoza, Cristina

2018-02-01

The aim of this study was to describe a case of severe keratitis-ichthyosis-deafness (KID) syndrome with ocular surface squamous neoplasia. The affected patient underwent complete ocular and systemic examinations. The molecular studies included polymerase chain reaction amplification and automated DNA sequencing of the complete gap junction beta-2 (GJB2) gene coding sequence. A 30-year-old man presented with generalized erythro-hyperkeratosis and deafness and complaints of decreased visual acuity, tearing, and photophobia. Ophthalmic examination showed corneal erosion, vascularization, and a gray gelatinous lesion partially covering the right cornea, suggestive of squamous neoplasia. The clinical features were characteristic of KID syndrome. This diagnosis was confirmed with a DNA analysis showing the pathogenic variant p.D50N in the GJB2 gene. Presumed squamous neoplasia was treated with topical interferon α2b. KID syndrome is a very rare disease that has been reported with an incremental incidence of squamous cell carcinoma of the mucous membranes and skin (12%-15%). Here, we presented a case of severe systemic KID syndrome with ocular surface squamous neoplasia.

Management of the ocular surface and tear film before, during, and after laser in situ keratomileusis.

PubMed

Albietz, Julie M; Lenton, Lee M

2004-01-01

To identify evidence-based, best practice strategies for managing the ocular surface and tear film before, during, and after laser in situ keratomileusis (LASIK). After a comprehensive review of relevant published literature, evidence-based recommendations for best practice management strategies are presented. Symptoms of ocular irritation and signs of dysfunction of the integrated lacrimal gland/ocular surface functional gland unit are common before and after LASIK. The status of the ocular surface and tear film before LASIK can impact surgical outcomes in terms of potential complications during and after surgery, refractive outcome, optical quality, patient satisfaction, and the severity and duration of dry eye after LASIK. Before LASIK, the health of the ocular surface should be optimized and patients selected appropriately. Dry eye before surgery and female gender are risk factors for developing chronic dry eye after LASIK. Management of the ocular surface during LASIK can minimize ocular surface damage and the risk of adverse outcomes. Long-term management of the tear film and ocular surface after LASIK can reduce the severity and duration of dry eye symptoms and signs. Strategies to manage the integrated ocular surface/lacrimal gland functional unit before, during, and after LASIK can optimize outcomes. As problems with the ocular surface and tear film are relatively common, attention should focus on the use and improvement of evidence-based management strategies.

Conjunctival Goblet Cell Function: Effect of Contact Lens Wear and Cytokines

PubMed Central

García-Posadas, Laura; Contreras-Ruiz, Laura; Soriano-Romaní, Laura; Dartt, Darlene A.; Diebold, Yolanda

2015-01-01

This review focuses on conjunctival goblet cells and their essential function in the maintenance of eye health. The main function of goblet cells is to produce and secrete mucins that lubricate the ocular surface. An excess or a defect in those mucins leads to several alterations that makes goblet cells central players in maintaining the proper mucin balance and ensuring the correct function of ocular surface tissues. A typical pathology that occurs with mucous deficiency is dry eye disease, whereas the classical example of mucous hyperproduction is allergic conjunctivitis. In this review we analyze how goblet cell number and function can be altered in these diseases and in contact lens wearers. We found that most published studies focused exclusively on goblet cell number. However, recent advances have demonstrated that, along with mucin secretion, goblet cells are also able to secrete cytokines and respond to them. We describe the effect of different cytokines on goblet cell proliferation and secretion. We conclude that it is important to further explore the effect of contact lens wear and cytokines on conjunctival goblet cell function. PMID:26067396

TFOS DEWS II pain and sensation report

PubMed Central

Belmonte, Carlos; Nichols, Jason J.; Cox, Stephanie M.; Brock, James A.; Begley, Carolyn G.; Bereiter, David A.; Dartt, Darlene A.; Galor, Anat; Hamrah, Pedram; Ivanusic, Jason J.; Jacobs, Deborah S.; McNamara, Nancy A.; Rosenblatt, Mark I.; Stapleton, Fiona; Wolffsohn, James S.

2017-01-01

Pain associated to mechanical and chemical irritation of the eye surface is mediated by trigeminal ganglia mechano- and polymodal nociceptor neurons while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of Meibonian gland secretion or mucins release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy. PMID:28736339

Caveolins and caveolae in ocular physiology and pathophysiology.

PubMed

Gu, Xiaowu; Reagan, Alaina M; McClellan, Mark E; Elliott, Michael H

2017-01-01

Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., "lipid rafts") have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signaling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function. Copyright © 2016 Elsevier Ltd. All rights reserved.

Caveolins and caveolae in ocular physiology and pathophysiology

PubMed Central

Gu, Xiaowu; Reagan, Alaina M.; McClellan, Mark E.; Elliott, Michael H.

2016-01-01

Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., “lipid rafts”) have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signalling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function. PMID:27664379

Effects of heat-treatment on plasma rich in growth factors-derived autologous eye drop.

PubMed

Anitua, E; Muruzabal, F; De la Fuente, M; Merayo-Lloves, J; Orive, G

2014-02-01

We have developed and characterized a new type of plasma rich in growth factors (PRGF) derived eye-drop therapy for patients suffering from autoimmune diseases. To determine the concentration of several growth factors, proteins, immunoglobulins and complement activity of the heat-inactivated eye-drop and to study its biological effects on cell proliferation and migration of different ocular surface cells, blood from healthy donors was collected, centrifuged and PRGF was prepared avoiding the buffy coat. The half volume of the obtained plasma supernatant from each donor was heat-inactivated at 56 °C for 1 h (heat-inactivated PRGF). The concentration of several proteins involved on corneal wound healing, immunoglubolins G, M and E and functional integrity of the complement system assayed by CH50 test were determined. The proliferative and migratory potential of inactivated and non-inactivated PRGF eye drops were assayed on corneal epithelial cells (HCE), keratocytes (HK) and conjunctival fibroblasts (HConF). Heat-inactivated PRGF preserves the content of most of the proteins and morphogens involved in its wound healing effects while reduces drastically the content of IgE and complement activity. Heat-inactivated PRGF eye drops increased proliferation and migration potential of ocular surface cells with regard to PRGF showing significant differences on proliferation and migration rate of HCE and HConF respectively. In summary, heat-inactivation of PRGF eye drops completely reduced complement activity and deceased significantly the presence of IgE, maintaining the biological activity of PRGF on ocular surface cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Correlation of corneal thickness, endothelial cell density and anterior chamber depth with ocular surface temperature in normal subjects.

PubMed

Pattmöller, Johanna; Wang, Jiong; Zemova, Elena; Seitz, Berthold; Eppig, Timo; Langenbucher, Achim; Szentmáry, Nóra

2015-09-01

To analyze corneal surface temperature profile in a young and healthy study population and to determine the impact of corneal thickness (CT), anterior chamber depth (ACD), and endothelial cell density (ECD) on surface temperature. In this prospective, single-center study 61 healthy right eyes of 61 subjects without tear film pathologies (mean age 24.9 ± 6.7 years) were recruited. Ocular surface temperature (OST) was measured with the Ocular Surface Thermographer TG-1000. From Pentacam HR CT and ACD, and from specular microscopy ECD and central corneal thickness (CCT) were acquired. From the raw measurement data (OST, CT and ACD) we extracted a) local OST the corneal center and 3mm away from the center at the 3, 6, and 9 o'clock positions, and b) Zernike parameters Z1, Z2 and Z3 to evaluate the general temperature profile within a 6mm circular area around the center. Overall, there was no correlation between OST and CT, ACD or ECD. Local OST did not correlate with CT at any measurement position. On average local OST was highest at measurement positions where CT was lowest, but without reaching statistical significance. Baseline OST was highest at thin corneal regions and temperature decay over time was smallest in those regions. Z1, Z2 and Z3 correlated well with CT. In healthy subjects corneal thickness, endothelial cell density and anterior chamber depth have no effect on corneal surface temperature. The general temperature profile seems to be influenced by the corneal thickness profile effecting a higher temperature and lower decay at thinner corneal regions. Copyright © 2014. Published by Elsevier GmbH.

Dry Eye Management: Targeting the Ocular Surface Microenvironment.

PubMed

Zhang, Xiaobo; M, Vimalin Jeyalatha; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo; Li, Wei

2017-06-29

Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment.

Dry Eye Management: Targeting the Ocular Surface Microenvironment

PubMed Central

Zhang, Xiaobo; Jeyalatha M, Vimalin; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo

2017-01-01

Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. PMID:28661456

Surgical Reconstruction of Ocular Surface Tumors Using Fibrin Sealant Tissue Adhesive.

PubMed

Queiroz de Paiva, Aline Roseane; Abreu de Azevedo Fraga, Larissa; Torres, Virgínia Laura Lucas

2016-10-01

To evaluate the surgical outcomes of ocular surface reconstruction in corneal-conjunctival tumors using fibrin tissue adhesive. A prospective noncomparative study was performed between May 2013 and February 2015. Patients were submitted to routine surgical procedure for corneal-conjunctival tumor excision followed by amniotic membrane graft transplantation using fibrin tissue adhesive (Evicel®, Omrix Biopharmaceuticals Ltd., Israel). Results were assessed on the 1st, 7th, 15th and 30th postoperative days to analyze subjective complaints, adhesiveness and positioning of the graft, potential complications and recurrences. Twenty-five eyes were analyzed (male, 14). The diagnosis after the treatment was categorized as squamous cell neoplasia, dysplasia, actinic keratosis, squamous papilloma and compound melanocytic nevus. Few significant symptoms were reported, such as mild hyperemia and ocular dyscomfort. One case developed a conjunctival granuloma which regressed after topical treatment. All grafts were successful with no displacements or retraction postoperatively. There was no clinical recurrence of the tumor in a mean time of follow-up of 11 months. Fibrin tissue adhesive is safe and effective in the surgery of ocular surface tumor. In this series, sutureless amniotic membrane transplantation using fibrin glue has the potential to shorten the surgical time, mitigate inflammation postoperatively and improve patient discomfort.

The pathology of dry eye: the interaction between the ocular surface and lacrimal glands.

PubMed

Stern, M E; Beuerman, R W; Fox, R I; Gao, J; Mircheff, A K; Pflugfelder, S C

1998-11-01

Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female. Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye. Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic. Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.

Ocular surface injury from a microwave superheated egg resulting in a pseudopterygium.

PubMed

Gagnon, Michael R; Dickinson, Paul J

2005-05-01

To describe the first case of ocular surface injury resulting in a pseudopterygium from a microwave superheated egg. Case report. A 12-year-old girl sustained an ocular surface injury resulting in a pseudopterygium from a microwave superheated egg. Microwave superheated eggs can result in ocular injury. This case illustrates the potential ocular danger involved with microwave ovens.

Nanoparticle Delivery of RNAi Therapeutics for Ocular Vesicant Injury

DTIC Science & Technology

2014-04-01

nanoparticles to smaller size with higher stability in physiological media, optimized a protocol to surface-coat nucleic acid nanoparticles with hyaluronic acid ...nanoparticle tissue retention and cell uptake by conjugating cell adhesion ligand to nanoparticles and by surface coating of hyaluronic acid to... hyaluronic acid , and retain the stability of the nanoparticles. Identified the conditions using reversible crosslinking density to stabilize siRNA

Regional differences in rat conjunctival ion transport activities

PubMed Central

Yu, Dongfang; Thelin, William R.; Rogers, Troy D.; Stutts, M. Jackson; Randell, Scott H.; Grubb, Barbara R.

2012-01-01

Active ion transport and coupled osmotic water flow are essential to maintain ocular surface health. We investigated regional differences in the ion transport activities of the rat conjunctivas and compared these activities with those of cornea and lacrimal gland. The epithelial sodium channel (ENaC), sodium/glucose cotransporter 1 (Slc5a1), transmembrane protein 16 (Tmem16a, b, f, and g), cystic fibrosis transmembrane conductance regulator (Cftr), and mucin (Muc4, 5ac, and 5b) mRNA expression was characterized by RT-PCR. ENaC proteins were measured by Western blot. Prespecified regions (palpebral, fornical, and bulbar) of freshly isolated conjunctival tissues and cell cultures were studied electrophysiologically with Ussing chambers. The transepithelial electrical potential difference (PD) of the ocular surface was also measured in vivo. The effect of amiloride and UTP on the tear volume was evaluated in lacrimal gland excised rats. All selected genes were detected but with different expression patterns. We detected αENaC protein in all tissues, βENaC in palpebral and fornical conjunctiva, and γENaC in all tissues except lacrimal glands. Electrophysiological studies of conjunctival tissues and cell cultures identified functional ENaC, SLC5A1, CFTR, and TMEM16. Fornical conjunctiva exhibited the most active ion transport under basal conditions amongst conjunctival regions. PD measurements confirmed functional ENaC-mediated Na+ transport on the ocular surface. Amiloride and UTP increased tear volume in lacrimal gland excised rats. This study demonstrated that the different regions of the conjunctiva exhibited a spectrum of ion transport activities. Understanding the specific functions of distinct regions of the conjunctiva may foster a better understanding of the physiology maintaining hydration of the ocular surface. PMID:22814399

Regional differences in rat conjunctival ion transport activities.

PubMed

Yu, Dongfang; Thelin, William R; Rogers, Troy D; Stutts, M Jackson; Randell, Scott H; Grubb, Barbara R; Boucher, Richard C

2012-10-01

Active ion transport and coupled osmotic water flow are essential to maintain ocular surface health. We investigated regional differences in the ion transport activities of the rat conjunctivas and compared these activities with those of cornea and lacrimal gland. The epithelial sodium channel (ENaC), sodium/glucose cotransporter 1 (Slc5a1), transmembrane protein 16 (Tmem16a, b, f, and g), cystic fibrosis transmembrane conductance regulator (Cftr), and mucin (Muc4, 5ac, and 5b) mRNA expression was characterized by RT-PCR. ENaC proteins were measured by Western blot. Prespecified regions (palpebral, fornical, and bulbar) of freshly isolated conjunctival tissues and cell cultures were studied electrophysiologically with Ussing chambers. The transepithelial electrical potential difference (PD) of the ocular surface was also measured in vivo. The effect of amiloride and UTP on the tear volume was evaluated in lacrimal gland excised rats. All selected genes were detected but with different expression patterns. We detected αENaC protein in all tissues, βENaC in palpebral and fornical conjunctiva, and γENaC in all tissues except lacrimal glands. Electrophysiological studies of conjunctival tissues and cell cultures identified functional ENaC, SLC5A1, CFTR, and TMEM16. Fornical conjunctiva exhibited the most active ion transport under basal conditions amongst conjunctival regions. PD measurements confirmed functional ENaC-mediated Na(+) transport on the ocular surface. Amiloride and UTP increased tear volume in lacrimal gland excised rats. This study demonstrated that the different regions of the conjunctiva exhibited a spectrum of ion transport activities. Understanding the specific functions of distinct regions of the conjunctiva may foster a better understanding of the physiology maintaining hydration of the ocular surface.

Clusterin in the eye: An old dog with new tricks at the ocular surface.

PubMed

Fini, M Elizabeth; Bauskar, Aditi; Jeong, Shinwu; Wilson, Mark R

2016-06-01

The multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

The tear film and ocular mucins.

PubMed

Davidson, Harriet J; Kuonen, Vanessa J

2004-01-01

Abstract The trilaminar tear film, composed of the lipid, aqueous and mucin layers, has many functions including defending the ocular surface. The aqueous layer has several soluble antimicrobial factors that protect the ocular surface. Ocular mucins have recently been studied with regard to their role in the defense of the eye as well as in dry eye syndromes. To date, 15 mucin genes have been identified, and six of these mucin genes are localized to or secreted by ocular glands or epithelia. Understanding the production, secretion and function of ocular mucins will aid in the treatment of dry eye syndromes and ocular surface microbial infections.

Ocular surface disease incidence in patients with open-angle glaucoma.

PubMed

Radenković, Marija; Stanković-Babić, Gordana; Jovanović, Predrag; Djordjević-Jocić, Jasmina; Trenkić-Božinović, Marija

2016-01-01

Ocular surface disease (OSD) is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbances, tear film instability with potential damage to the ocular surface, accompanied by increased tear film osmolarity and inflammation of the ocular surface. It is a consequence of disrupted homeostasis of lacrimal functional unit. The main pathogenetic mechanism stems from tear hyperosmolarity and tear film instability. The etiological classification is hyposecretory (Sy-Sjögren and non-Sjögren) and evaporative (extrinsic and intrinsic) form. Delphi panel classification grades disease stages. Antiglaucoma topical therapy causes exacerbation or occurrence of symptoms of dry eye due to main ingredients or preservatives (benzalkonium chloride – BAK), which are dose- and time-dependent. BAK reduces the stability of the lipid layer of tears, the number of goblet cells, induces apoptosis and inflammatory infiltration. The aim of this study was the analysis of the OSD incidence in open-angle glaucoma patients caused by topical medicamentous therapy. Retrospective analysis of examined patients with open-angle glaucoma was used. Increased incidence of moderate and advanced OSD Index degrees in the group of primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma. According to the Delphi Panel Scale the most common grade is IIb (POAG and pseudoexfoliative glaucoma). Evaporative form of OSD prevailed in all treatment groups. High percentage of dry eye in patients with higher concentrations of preservatives applied was noticed. OSD should be timely diagnosed and treated. Dry eye has an impact on surgical outcome and postoperative visual acuity, and in order to improve patient compliance and quality of life, symptoms of dry eye should be addressed and medications with lower concentrations of preservatives should be applied.

Prevalence of dry eye syndrome after allogeneic hematopoietic stem cell transplantation.

PubMed

Ivanir, Yair; Shimoni, Avichai; Ezra-Nimni, Orit; Barequet, Irina S

2013-05-01

To evaluate the prevalence, severity, and effect of dry eye in patients after allogeneic hematopoietic stem cell transplantation (aHSCT) and to correlate the findings to the duration after transplantation. A total of 222 eyes of 111 patients after aHSCT at the Department of Bone Marrow Transplantation, Sheba Medical Center, Israel in a consecutive 3-year period. All patients underwent a full ophthalmic examination and filled the ocular surface disease index (OSDI) questionnaire to assess ocular involvement in the form of dry eye syndrome or any other ocular manifestation. The main outcome measures were best-corrected visual acuity, tear break-up time, corneal fluorescein staining, Schirmer test, and OSDI questionnaire. A total of 111 patients were recruited. In 37%, a diagnosis of ocular graft versus host disease was previously made and 46% had no previous ocular examination. Schirmer test was less than 5 mm in 50% of all patients, and in 30% of patients with undiagnosed ocular involvement. The mean OSDI score was 13, and in 28% it was above 20. Correlation was found between visual acuity decrease and high OSDI score to the diagnosis of ocular graft versus host disease and signs of dry eye syndrome. A trend of worsening dry eye was observed up to the second half of the second year posttransplantation. Although many patients are either asymptomatic or do not seek ophthalmic examination, severe dry eye is a common finding after aHSCT. Mandatory follow-up, patient education, and early treatment may improve the quality of life.

Nitric oxide secretion in human conjunctival fibroblasts is inhibited by alpha linolenic acid.

PubMed

Erdinest, Nir; Shohat, Noam; Moallem, Eli; Yahalom, Claudia; Mechoulam, Hadas; Anteby, Irene; Ovadia, Haim; Solomon, Abraham

2015-01-01

It is known that both human conjunctival fibroblasts (HCF) and corneal epithelial (HCE) cells contribute to the inflammatory process in the ocular surface by releasing inflammatory cytokines. In addition, nitric oxide (NO) has an important role in inflammatory responses in the ocular surface. In the present study, we aimed to characterize the capacity of these cells to release nitric oxide in response to cytokines and Lipopolysaccharide (LPS), and show that Alpha-linoleic acid (ALA) inhibits these responses. HCF, HCE cells, peripheral blood mononuclear cells (PBMCs) and co-culture of HCF and PBMC were treated with different combinations of inflammatory inducers, including interleukin)IL- (6, tumor necrosis factors (TNF)-α, interferon (IFN)- γ and IL-1β and LPS. Nitrite levels were measured in cell supernatants with and without ALA by the Griess reaction test at 24, 48 and 72 h respectively. Expression of nitric oxide synthase 2 (NOS-2) was evaluated by real-time PCR. All cytokine combinations had an inducible effect on nitrite secretion in HCF, PBMC and co-cultured PBMC and HCF, but not in HCE cells. Treatment with a combination of IL-6, LPS, TNF-α, IFN- γ and IL-1β induced the highest nitrite secretion (2.91 fold, P < 0.01) as compared to cells incubated in medium alone. nitrite secretion was reduced by 38.9 % (P < 0.05) after treatment with ALA alone. Co-culturing PBMC with HCF with and without ALA treatment demonstrated similar results in nitrite level as,compared to PBMC alone. In addition, ALA significantly decreased NOS-2 expression in HCF by 48.9 % (P < 0. 001) after 72 h. The decrease in nitrite release and inhibition of NOS-2 expression indicate that ALA may have an anti-inflammatory effect both on HCF and on peripheral immune cells. This indicates that ALA may serve as a potent anti-inflammatory agent in ocular surface inflammation.

Development of Causative Treatment Strategies for Lacrimal Gland Insufficiency by Tissue Engineering and Cell Therapy. Part 2: Reconstruction of Lacrimal Gland Tissue: What Has Been Achieved So Far and What Are the Remaining Challenges?

PubMed

Massie, Isobel; Dietrich, Jana; Roth, Mathias; Geerling, Gerd; Mertsch, Sonja; Schrader, Stefan

2016-10-01

The lacrimal gland is located in the upper temporal compartment of the orbita, and along with the ocular surface, eye lids, and sensory and motor nerves forms the lacrimal functional unit (LFU). The LFU is responsible for producing, distributing, and maintaining the tear film in order to maintain a smooth, moist, and regular ocular surface epithelium such that appropriate refractive properties are achieved and the eyeball is protected against dust, debris, and pathogens. If the main lacrimal gland is impaired (due to either disease or injury), this balance is disrupted, and severe quantitative dry eye syndrome (DES) can develop. DES treatments remain palliative, with the most commonly used therapies being based on tear substitution, tear retention, and control of inflammation on the ocular surface. Causative treatments such as salivary gland transplantation have shown to reduce symptoms in very severe cases, however can cause problems on the ocular surface due to different properties of saliva and tears. Therefore, causative approaches for treating DES by regeneration or reconstruction of lacrimal gland tissue depending on disease severity seem highly appealing. This article reviews current approaches for in vitro reconstruction of lacrimal gland tissue. Finally, the limitations that must be overcome before a new, tissue-engineered therapy may be delivered to clinic will be discussed.

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways.

PubMed

Ru, Yusha; Huang, Yue; Liu, Huijuan; Du, Juan; Meng, Zhu; Dou, Zexia; Liu, Xun; Wei, Rui Hua; Zhang, Yan; Zhao, Shaozhen

2015-12-21

Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10(-4) μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH's protective effects, suggesting that both pathways are necessary for α-MSH's protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED.

α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

PubMed Central

Ru, Yusha; Huang, Yue; Liu, Huijuan; Du, Juan; Meng, Zhu; Dou, Zexia; Liu, Xun; Wei, Rui Hua; Zhang, Yan; Zhao, Shaozhen

2015-01-01

Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10−4 μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH’s protective effects, suggesting that both pathways are necessary for α-MSH’s protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED. PMID:26685899

Incorporation of liquid lipid in lipid nanoparticles for ocular drug delivery enhancement

NASA Astrophysics Data System (ADS)

Shen, Jie; Sun, Minjie; Ping, Qineng; Ying, Zhi; Liu, Wen

2010-01-01

The present work investigates the effect of liquid lipid incorporation on the physicochemical properties and ocular drug delivery enhancement of nanostructured lipid carriers (NLCs) and attempts to elucidate in vitro and in vivo the potential of NLCs for ocular drug delivery. The CyA-loaded or fluorescein-marked nanocarriers composed of Precifac ATO 5 and Miglyol 840 (as liquid lipid) were prepared by melting-emulsion technology, and the physicochemical properties of nanocarriers were determined. The uptake of nanocarriers by human corneal epithelia cell lines (SDHCEC) and rabbit cornea was examined. Ex vivo fluorescence imaging was used to investigate the ocular distribution of nanocarriers. The in vitro cytotoxicity and in vivo acute tolerance were evaluated. The higher drug loading capacity and improved in vitro sustained drug release behavior of lipid nanoparticles was found with the incorporation of liquid lipid in lipid nanoparticles. The uptake of nanocarriers by the SDHCEC was increased with the increase in liquid lipid loading. The ex vivo fluorescence imaging of the ocular tissues indicated that the liquid lipid incorporation could improve the ocular retention and penetration of ocular therapeutics. No alternation was macroscopically observed in vivo after ocular surface exposure to nanocarriers. These results indicated that NLC was a biocompatible and potential nanocarrier for ocular drug delivery enhancement.

A novel pressed porous silicon-polycaprolactone composite as a dual-purpose implant for the delivery of cells and drugs to the eye.

PubMed

Irani, Yazad D; Tian, Yuan; Wang, Mengjia; Klebe, Sonja; McInnes, Steven J; Voelcker, Nicolas H; Coffer, Jeffery L; Williams, Keryn A

2015-10-01

Dysfunction of corneal epithelial stem cells can result in painful and blinding disease of the ocular surface. In such cases, treatment may involve transfer of growth factor and normal adult stem cells to the ocular surface. Our purpose was to develop an implantable scaffold for the delivery of drugs and cells to the ocular surface. We examined the potential of novel composite biomaterials fabricated from electrospun polycaprolactone (PCL) fibres into which nanostructured porous silicon (pSi) microparticles of varying sizes (150-250 μm or <40 μm) had been pressed. The PCL fabric provided a flexible support for mammalian cells, whereas the embedded pSi provided a substantial surface area for efficient delivery of adsorbed drugs and growth factors. Measurements of tensile strength of these composites revealed that the pSi did not strongly influence the mechanical properties of the polymer microfiber component for the Si loadings evaluated. Human lens epithelial cells (SRA01/04) attached to the composite materials, and exhibited enhanced attachment and growth when the materials were coated with foetal bovine serum. To examine the ability of the materials to deliver a small-drug payload, pSi microparticles were loaded with fluorescein diacetate prior to cell attachment. After 6 hours (h), cells exhibited intracellular fluorescence, indicative of transfer of the fluorescein diacetate into viable cells and its subsequent enzymatic conversion to fluorescein. To investigate loading of large-molecule biologics, murine BALB/c 3T3 cells, responsive to epidermal growth factor, insulin and transferrin, were seeded on composite materials. The cells showed significantly more proliferation at 48 h when seeded on composites loaded with these biologics, than on unloaded composites. No cell proliferation was observed on PCL alone, indicating the biologics had loaded into the pSi microparticles. Drug release, measured by ELISA for insulin, indicated a burst followed by a slower, continuous release over six days. When implanted under the rat conjunctiva, the most promising composite material did not cause significant neovascularization but did elicit a macrophage and mild foreign body response. These novel pressed pSi-PCL materials have potential for delivery of both small and large drugs that can be released in active form, and can support the growth of mammalian cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Understanding the Presence and Roles of Ap4A (Diadenosine Tetraphosphate) in the Eye.

PubMed

Crooke, Almudena; Guzman-Aranguez, Ana; Carracedo, Gonzalo; de Lara, Maria J Perez; Pintor, Jesus

Diadenosine tetraphosphate abbreviated Ap 4 A is a naturally occurring dinucleotide, which is present in most of the ocular fluids. Due to its intrinsic resistance to enzyme degradation compared to mononucleotides, this molecule can exhibit profound actions on ocular tissues, including the ocular surface, ciliary body, trabecular meshwork, and probably the retina. The actions of Ap 4 A are mostly carried out by P2Y 2 receptors, but the participation of P2X2 and P2Y 6 in processes such as the regulation of intraocular pressure (IOP), together with the P2Y 2 , is pivotal. Beyond the physiological role, this dinucleotide can present on the ocular surface keeping a right production of tear secretion or regulating IOP. It is important to note that exogenous application of Ap 4 A to cells or animal models can significantly modify pathophysiological conditions and thus is an attractive therapeutic molecule. The ocular location where Ap 4 A actions have not been fully elucidated is in the retina. Although some analogues show interesting actions on pathological situations such as retinal detachment, little is known about the real effect of this dinucleotide, this being one of the challenges that require pursuing in the near future.

Emerging treatment paradigms of ocular surface disease: proceedings of the Ocular Surface Workshop.

PubMed

Rolando, M; Geerling, G; Dua, H S; Benítez-del-Castillo, J M; Creuzot-Garcher, C

2010-01-01

The objective of the Ocular Surface Workshop in Rome, Italy, on 6 February 2009, was to enhance the understanding of ocular surface disease (OSD) through an exploration of the nature of its complexities and current treatment paradigms across Europe. It was hoped that the peer-to-peer discussions and updates regarding common knowledge, clinical practices and shared experiences at this workshop would subsequently shape future treatment approaches to OSD.

Spdef null mice lack conjunctival goblet cells and provide a model of dry eye.

PubMed

Marko, Christina K; Menon, Balaraj B; Chen, Gang; Whitsett, Jeffrey A; Clevers, Hans; Gipson, Ilene K

2013-07-01

Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef(-/-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Effect of bilastine upon the ocular symptoms of allergic rhinoconjunctivitis.

PubMed

Bartra, J; Mullol, J; Montoro, J; Jáuregui, I; del Cuvillos, A; Dávila, I; Ferrer, M; Sastre, J; Valero, A

2011-01-01

Ocular symptoms often accompany allergic rhinitis and can be as or even more bothersome for the patient than the actual nasal symptoms. Ocular manifestations of allergic rhinoconjunctivitis may result from both direct allergen-mediated mast cell stimulation on the surface of the eye and naso-ocular reflexes--histamine being one of the mediators of symptoms onset. An H1 antihistamine would be the first line treatment for allergic conjunctivitis. Since allergic conjunctivitis is always (or almost always) accompanied by nasal symptoms, a second-generation H1 antihistamine administered via oral route is the drug of choice for jointly managing both the nasal and the ocular symptoms--minimizing the impact of the effects inherent to first-generation H, antihistamine, including particularly drowsiness. Bilastine is a new H1 antihistamine with an excellent safety profile, developed for the treatment of allergic rhinoconjunctivitis and urticaria, with potency similar to that of cetirizine and desloratadine, and superior to that of fexofenadine. This new drug has been shown to be effective in controlling the ocular symptoms of allergic rhinoconjunctivitis.

Long term safety and tolerability of Tafluprost 0.0015% vs Timolol 0.1% preservative-free in ocular hypertensive and in primary open-angle glaucoma patients: a cross sectional study.

PubMed

Rolle, Teresa; Spinetta, Roberta; Nuzzi, Raffaele

2017-08-03

The effects of preservatives of antiglaucoma medications on corneal surface and tear function have been widely shown in literature; it's not the same as regards the active compounds themselves. The purpose of our study was to compare Ocular Surface Disease (OSD) signs and symptoms of Tafluprost 0.0015% versus preservative free (PF) Timolol 0.1% eyedrops in ocular hypertensive (OH) and in primary open-angle glaucoma (POAG) patients. A cross-sectional study included patients in monotherapy for at least 36 months with Tafluprost 0.0015% (27) or PF Timolol 0.1% (24) and 20 healthy age and sex-matched volunteers. All subjects underwent clinical tests (Schirmer I and break-up time), in vivo confocal microscopy (IVCM) and were surveyed using Ocular Surface Disease Index (OSDI) and Glaucoma Symptoms Scale (GSS) questionnaires. The groups were compared with ANOVA, Kruskal-Wallis test, t-test, Mann-Whitney test and Bonferroni's adjustment of p-values. No significant differences were found in questionnaires scores, clinical tests, IVCM variables between therapy groups. Tafluprost 0.0015% group showed significantly higher OSDI score, basal epithelial cells density, stromal reflectivity, sub-basal nerves tortuosity (p = 0.0000, 0.037, 0.006, 0.0000) and less GSS score, number of sub-basal nerves (p = 0.0000, 0.037) than controls but similar clinical tests results (p > 0.05). PF Timolol group had significantly higher OSDI score, basal epithelial cells density, stromal reflectivity and sub-basal nerve tortuosity (p = 0.000, 0.014, 0.008, 0.002), less GSS score, BUT and number of sub-basal nerves (p = 0.0000, 0.026, 0.003) than controls. Compared to PF Timolol 0.1%, Tafluprost 0.0015% showed similar safety with regards to tear function and corneal status and a similar tolerability profile. Both therapy groups show some alterations in corneal microstructure but no side effects on tear function except for an increased tear instability in PF Timolol 0.1% group. Ophtalmologists should be aware that even PF formulations may lead to a mild ocular surface impairment.

Spdef Null Mice Lack Conjunctival Goblet Cells and Provide a Model of Dry Eye

PubMed Central

Marko, Christina K.; Menon, Balaraj B.; Chen, Gang; Whitsett, Jeffrey A.; Clevers, Hans; Gipson, Ilene K.

2014-01-01

Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef−/− mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef−/− mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef−/− mice revealed down-regulation of goblet cell–specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef−/− mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. PMID:23665202

Chronic Dry Eye Disease is Principally Mediated by Effector Memory Th17 Cells

PubMed Central

Chen, Yihe; Chauhan, Sunil K.; Lee, Hyun Soo; Saban, Daniel R.; Dana, Reza

2013-01-01

Recent experimental and clinical data suggest that there is a link between dry eye disease (DED) and T cell-mediated immunity. However, whether these immune responses are a consequence or cause of ocular surface inflammation remains to be determined. Thus far, only models of acute DED have been used to derive experimental data. This is in contrast to clinical DED which usually presents as a chronic disease. In the present study, using a murine model of chronic DED, it was established that the chronic phase of the disease is accompanied by Th17 responses at the ocular surface, and that a significant memory T cell population can be recovered from chronic DED. This memory response is predominantly mediated by Th17 cells. Moreover, adoptive transfer of this memory T cell population was shown to induce more severe and rapidly progressing DED than did the adoptive transfer of its effector or naïve counterparts. Not only do these results clearly demonstrate that effector memory Th17 cells are primarily responsible for maintaining the chronic and relapsing course of DED, but they also highlight a potentially novel therapeutic strategy for targeting memory immune responses in patients with DED. PMID:23571503

In utero eyeball development study by magnetic resonance imaging.

PubMed

Brémond-Gignac, D S; Benali, K; Deplus, S; Cussenot, O; Ferkdadji, L; Elmaleh, M; Lassau, J P

1997-01-01

The aim of this study was to measure fetal ocular development and to determine a growth curve by means of measurements in utero. Fetal ocular development was recorded by analysis of the results of magnetic resonance imaging (MRI). An anatomic study allowed definition of the best contrasted MRI sequences for calculation of the ocular surface. Biometric analysis of the values of the ocular surface in the neuro-ocular plane in 35 fetuses allowed establishment of a linear model of ocular growth curve in utero. Evaluation of ocular development may allow the detection and confirmation of malformational ocular anomalies such as microphthalmia.

The application of autologous serum eye drops in severe dry eye patients; subjective and objective parameters before and after treatment.

PubMed

Jirsova, Katerina; Brejchova, Kristyna; Krabcova, Ivana; Filipec, Martin; Al Fakih, Aref; Palos, Michalis; Vesela, Viera

2014-01-01

To assess the impact of autologous serum (AS) eye drops on the ocular surface of patients with bilateral severe dry eye and to draw a comparison between the clinical and laboratory examinations and the degree of subjective symptoms before and after serum treatment. A three-month prospective study was conducted on 17 patients with severe dry eye. AS eye drops were applied a maximum of 12 times a day together with regular therapy. Dry eye status was evaluated by clinical examination (visual acuity, Schirmer test, tear film breakup time, vital staining, tear film debris and meniscus), conjunctival impression cytology (epithelial and goblet cell density, snake-like chromatin, HLA-DR-positive and apoptotic cells) and subjectively by the patients. The application of AS eye drops led to a significant improvement in the Schirmer test (p < 0.01) and tear film debris (p < 0.05). The densities of goblet (p < 0.0001) and epithelial cells (p < 0.05) were significantly increased, indicating a decrease of squamous metaplasia after AS treatment. A significant decrease (p < 0.05) was found in the number of apoptotic, HLA-DR-positive and snake-like chromatin cells on the ocular surface. A significant improvement was found in all evaluated subjective symptoms. Altogether, the clinical results were improved in 77%, the laboratory results in 75% and the subjective feelings in 63% of the eyes. We found that three-month AS treatment led especially to the improvement of ocular surface dryness and damage of the epithelium. The improvement of dry eye after AS treatment correlated well with the clinical, laboratory and subjective findings. From the patients' subjective point of view, the positive effect of AS decreased with time, but still persisted up to three months after the end of therapy.

A systematic review on the impact of diabetes mellitus on the ocular surface

PubMed Central

Shih, K Co; Lam, K S-L; Tong, L

2017-01-01

Diabetes mellitus is associated with extensive morbidity and mortality in any human community. It is well understood that the burden of diabetes is attributed to chronic progressive damage in major end-organs, but it is underappreciated that the most superficial and transparent organ affected by diabetes is the cornea. Different corneal components (epithelium, nerves, immune cells and endothelium) underpin specific systemic complications of diabetes. Just as diabetic retinopathy is a marker of more generalized microvascular disease, corneal nerve changes can predict peripheral and autonomic neuropathy, providing a window of opportunity for early treatment. In addition, alterations of immune cells in corneas suggest an inflammatory component in diabetic complications. Furthermore, impaired corneal epithelial wound healing may also imply more widespread disease. The non-invasiveness and improvement in imaging technology facilitates the emergence of new screening tools. Systemic control of diabetes can improve ocular surface health, possibly aided by anti-inflammatory and vasoprotective agents. PMID:28319106

Histological observation of goblet cells following topical rebamipide treatment of the human ocular surface: A case report.

PubMed

Kase, Satoru; Shinohara, Toshiya; Kase, Manabu

2015-02-01

The topical administration of rebamipide (Mucosta®), an antiulcer agent, clinically increases the mucin level of tear film. The aim of this study was to report the histological changes of goblet cells following the topical administration of rebamipide to a patient with nevus of the lacrimal caruncle. A 62-year-old male exhibited a pigmented nodule located in the lacrimal caruncle in the left eye. An excisional biopsy and subsequent surgical resection were conducted at the caruncle, prior to and three months after topical rebamipide administration. Histologically, a biopsy specimen revealed a pigmented nevus beneath the caruncle epithelium containing a few goblet cells [4 cells/high power field (HPF)]. A few nevus cells were present at the surgical margin. By contrast, the secondary resected specimen obtained three months after the initiation of topical rebamipide treatment revealed the epithelium and nevus, where numerous goblet cells were present (28 cells/HPF), and mucin-like substances were markedly secreted from the goblet cells. Topical rebamipide markedly increased the number of goblet cells and stimulated the secretion of mucin-like substances in the caruncular tissue of a human patient. These results suggest that topical rebamipide is useful in patients following surgery and/or biopsy to support tissue repair of the ocular surface.

[Study of ocular surface electromyography signal analysis].

PubMed

Zhu, Bei; Qi, Li-Ping

2009-11-01

Test ocular surface electromyography signal waves and characteristic parameters to provide effective data for the diagnosis and treatment of ocular myopathy. Surface electromyography signals tests were performed in 140 normal volunteers and 30 patients with ophthalmoplegia. Surface electrodes were attached to medial canthi, lateral canthi and the middle of frontal bone. Then some alternate flashing red lamps were installed on perimeter to reduce the movement of eyeball. The computer hardware, software, and A/D adapter (12 Bit) were used. Sampling frequency could be selected within 40 kHz, frequency of amplifier was 2 kHz, and input short circuit noise was less than 3 microV. For normal volunteers, the ocular surface electromyography signals were regular, and the electric waves were similar between different sex groups and age groups. While for patients with ophthalmoplegia, the wave amplitude of ocular surface electromyography signals were declined or disappeared in the dyskinesia direction. The wave amplitude was related with the degree of pathological process. The characteristic parameters of patients with ophthalmoplegia were higher than normal volunteers. The figures of ocular surface electromyogram obtained from normal volunteers were obviously different with that from patients with ophthalmoplegia. This test can provide reliable quantized data for the diagnosis and treatment of ocular myopathy.

Conjugation of cell-penetrating peptides with poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles improves ocular drug delivery

PubMed Central

Vasconcelos, Aimee; Vega, Estefania; Pérez, Yolanda; Gómara, María J; García, María Luisa; Haro, Isabel

2015-01-01

In this work, a peptide for ocular delivery (POD) and human immunodeficiency virus transactivator were conjugated with biodegradable poly(lactic-co-glycolic acid) (PGLA)–polyethylene glycol (PEG)-nanoparticles (NPs) in an attempt to improve ocular drug bioavailability. The NPs were prepared by the solvent displacement method following two different pathways. One involved preparation of PLGA NPs followed by PEG and peptide conjugation (PLGA-NPs-PEG-peptide); the other involved self-assembly of PLGA-PEG and the PLGA-PEG-peptide copolymer followed by NP formulation. The conjugation of the PEG and the peptide was confirmed by a colorimetric test and proton nuclear magnetic resonance spectroscopy. Flurbiprofen was used as an example of an anti-inflammatory drug. The physicochemical properties of the resulting NPs (morphology, in vitro release, cell viability, and ocular tolerance) were studied. In vivo anti-inflammatory efficacy was assessed in rabbit eyes after topical instillation of sodium arachidonate. Of the formulations developed, the PLGA-PEG-POD NPs were the smaller particles and exhibited greater entrapment efficiency and more sustained release. The positive charge on the surface of these NPs, due to the conjugation with the positively charged peptide, facilitated penetration into the corneal epithelium, resulting in more effective prevention of ocular inflammation. The in vitro toxicity of the NPs developed was very low; no ocular irritation in vitro (hen’s egg test–chorioallantoic membrane assay) or in vivo (Draize test) was detected. Taken together, these data demonstrate that PLGA-PEG-POD NPs are promising vehicles for ocular drug delivery. PMID:25670897

[Ocular surface system integrity].

PubMed

Safonova, T N; Pateyuk, L S

2015-01-01

The interplay of different structures belonging to either the anterior segment of the eye or its accessory visual apparatus, which all share common embryological, anatomical, functional, and physiological features, is discussed. Explanation of such terms, as ocular surface, lacrimal functional unit, and ocular surface system, is provided.

Effects of Exposure to Ozone on the Ocular Surface in an Experimental Model of Allergic Conjunctivitis

PubMed Central

Lee, Hun; Kim, Eung Kweon; Kim, Hee Young; Kim, Tae-im

2017-01-01

Based on previous findings that ozone can induce an inflammatory response in the ocular surface of an animal model and in cultured human conjunctival epithelial cells, we investigated whether exposure to ozone exacerbates symptoms of allergic conjunctivitis. We evaluated the effects of exposure to ozone on conjunctival chemosis, conjunctival injection, corneal and conjunctival fluorescein staining scores, production of inflammatory cytokines in tears, and aqueous tear production in a mouse model of allergic conjunctivitis. To validate our in vivo results, we used interleukin (IL)-1α-pretreated conjunctival epithelial cells as an in vitro substitute for the mouse model. We evaluated whether exposure to ozone increased the inflammatory response and altered oxidative status and mitochondrial function in IL-1α-pretreated conjunctival epithelial cells. In the in vivo study, ozone induced increases in conjunctival chemosis, conjunctival injection, corneal and conjunctival fluorescein staining scores, and production of inflammatory cytokines, accompanied by a decrease in tear volume. In the in vitro study, exposure to ozone led to additional increases in IL-6 and tumor necrosis factor-α mRNA levels, which were already induced by treatment with IL-1α. Ozone did not induce any changes in cell viability. Pretreatment with IL-1α increased the expression of manganese superoxide dismutase, and exposure to ozone led to additional increments in the expression of this antioxidant enzyme. Ozone did not induce any changes in mitochondrial activity or expression of mitochondrial enzymes and proteins related to mitochondrial function, with the exception of phosphor-mammalian target of rapamycin. Treatment with butylated hydroxyanisole, a free radical scavenger, attenuated the ozone-induced increases in IL-6 expression in IL-1α-pretreated conjunctival epithelial cells. Therefore, we conclude that exposure to ozone exacerbates the detrimental effects on the integrity of the ocular surface caused by conjunctival allergic reactions, and further increases the inflammatory response in IL-1α-pretreated conjunctival epithelial cells. PMID:28046113

Toxicity of cosmetic preservatives on human ocular surface and adnexal cells.

PubMed

Chen, Xiaomin; Sullivan, David A; Sullivan, Amy Gallant; Kam, Wendy R; Liu, Yang

2018-05-01

Cosmetic products, such as mascara, eye shadow, eyeliner and eye makeup remover are used extensively to highlight the eyes or clean the eyelids, and typically contain preservatives to prevent microbial growth. These preservatives include benzalkonium chloride (BAK) and formaldehyde (FA)-releasing preservatives. We hypothesize that these preservatives, at concentrations (BAK = 1 mg/ml; FA = 0.74 mg/ml) approved for consumer use, are toxic to human ocular surface and adnexal cells. Accordingly, we tested the influence of BAK and FA on the morphology, survival, and proliferation and signaling ability of immortalized human meibomian gland (iHMGECs), corneal (iHCECs) and conjunctival (iHConjECs) epithelial cells. iHMGECs, iHCECs and iHConjECs were cultured with different concentrations of BAK (5 μg/ml to 0.005 μg/ml) or FA (1 mg/ml to 1 μg/ml) under basal, proliferating or differentiating conditions up to 7 days. We used low BAK levels, because we found that 0.5 mg/ml and 50 μg/ml BAK killed iHMGECs within 1 day after a 15 min exposure. Experimental procedures included analyses of cell appearance, cell number, and neutral lipid content (LipidTox), lysosome accumulation (LysoTracker) and AKT signaling in all 3 cell types. Our results demonstrate that BAK and FA cause dose-dependent changes in the morphology, survival, proliferation and AKT signaling of iHMGECs, iHCECs and iHConjECs. Many of the concentrations tested induced cell atrophy, poor adherence, decreased proliferation and death, after 5 days of exposure. Cellular signaling, as indicated by AKT phosphorylation after 15 (FA) or 30 (BAK) minutes of treatment, was also reduced in a dose-dependent fashion in all 3 cell types, irrespective of whether cells had been cultured under proliferating or differentiating conditions. Our results support our hypothesis and demonstrate that the cosmetic preservatives, BAK and FA, exert many toxic effects on cells of the ocular surface and adnexa. Copyright © 2018 Elsevier Ltd. All rights reserved.

The ocular lesions of naturally occurring lymphocystis in fish.

PubMed

Dukes, T W; Lawler, A R

1975-10-01

Six cases of ocular lymphocystis, a virus disease, are described. Lymphocystis is generally known as a benigh, unique, giant cell disease of fishes causing nodules on the skin and fins. It has been studied extensively because of the virus-host cell relationship that results in extreme size and lack of quick cellular destruction or stimulation to neoplasia. Lymphocystis cells were found behind or in one or both eyes and were also found on the cornea or adjacent skin surfaces. A retrobulbar mass produced extreme exophthalmos. Uveal (choroid and iris) masses were present in most cases. Optic nerve involvement was also seen. It is probable that the virus reached the eye by the blood with the resulting masses forming in situ rather than by direct extension from skin lesions.

Mini-Review: Limbal Stem Cells Deficiency in Companion Animals: Time to Give Something Back?

PubMed

Sanchez, Rick F; Daniels, Julie T

2016-04-01

Experimental animals have been used extensively in the goal of developing sight-saving therapies for humans. One example is the development of transplantation of cultured limbal epithelial stem cells (LESC) to restore vision following ocular surface injury or disease. With clinical trials of cultured LESC therapy underway in humans and a potential companion animal population suffering from similar diseases, it is perhaps time to give something back. Comparatively to humans, what is known about the healthy limbus and corneal surface physiology of companion animals is still very little. Blinding corneal diseases in animals such as symblepharon in cats with Feline Herpes Virus-1 infections require a basic understanding of the functional companion animal limbus and corneal stem cells. Our understanding of many other vision threatening conditions such as scarring of the cornea post-inflammation with lymphocytic-plasmacytic infiltrate in dogs (aka chronic superficial keratitis) or pigment proliferation with Pigmentary Keratitis of Pugs would benefit from a better understanding of the animal cornea in health and disease. This is also vital when new therapeutic approaches are considered. This review will explore the current challenges and future research directions that will be required to increase our understanding of corneal diseases in animals and consider the potential development and delivery of cultured stem cell therapy to veterinary ocular surface patients.

Neurturin-deficient mice develop dry eye and keratoconjunctivitis sicca.

PubMed

Song, Xiu Jun; Li, De-Quan; Farley, William; Luo, Li Hui; Heuckeroth, Robert O; Milbrandt, Jeffrey; Pflugfelder, Stephen C

2003-10-01

Neurturin has been identified as a neurotrophic factor for parasympathetic neurons. Neurturin-deficient (NRTN(-/-)) mice have defective parasympathetic innervation of their lacrimal glands. This study was conducted to evaluate tear function and ocular surface phenotype in NRTN(-/-) mice. Determined by tail genomic DNA PCR, 25 NRTN(-/-) mice and 17 neurturin-normal (NRTN(+/+)) mice aged 6 weeks to 4 months were evaluated. Aqueous tear production, tear fluorescein clearance and corneal sensation were serially measured. Corneal permeability to AlexaFluor dextran (AFD; Molecular Probes, Eugene, OR) was measured by a fluorometric assay at 485 nm excitation and 530 nm emission. Histology was evaluated in PAS-stained sections. Mucin and HLA class II (IA) antigen were assessed by immunofluorescent staining. Tear IL-1beta was measured by ELISA, and tear matrix metalloproteinase (MMP)-9 by zymography. Gene expression in the corneal epithelia was analyzed by semiquantitative RT-PCR. In comparison to that in age-matched NRTN(+/+) mice, aqueous tear production, tear fluorescein clearance, and corneal sensation were significantly reduced in NRTN(-/-) mice, whereas corneal permeability to AFD was significantly increased. Immunoreactive MUC-4 and -5AC mucin and goblet cell density (P < 0.001) in the conjunctiva of NRTN(-/-) mice were lower than in NRTN(+/+) mice. The expression of MUC-1 and -4 mRNA by the corneal epithelium was reduced in NRTN(-/-) mice. There were a significantly greater number of IA antigen-positive conjunctival epithelial cells in NRTN(-/-) mice than NRTN(+/+) mice. Tear fluid IL-1beta and MMP-9 concentrations and the expression of IL-1beta, TNF-alpha, macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (KC), and MMP-9 mRNA by the corneal epithelia were significantly increased in NRTN(-/-) mice, compared with NRTN(+/+) mice. Neurturin-deficient mice show phenotypic changes and ocular surface inflammation that mimic human keratoconjunctivitis sicca. This model supports the importance of a functional ocular surface-central nervous system-lacrimal gland sensory-autonomic neural network in maintaining ocular surface health and homeostasis.

Lipoxin A4 Counter-regulates Histamine-stimulated Glycoconjugate Secretion in Conjunctival Goblet Cells.

PubMed

Hodges, Robin R; Li, Dayu; Shatos, Marie A; Serhan, Charles N; Dartt, Darlene A

2016-11-08

Conjunctival goblet cells synthesize and secrete mucins which play an important role in protecting the ocular surface. Pro-resolution mediators, such as lipoxin A 4 (LXA 4 ), are produced during inflammation returning the tissue to homeostasis and are also produced in non-inflamed tissues. The purpose of this study was to determine the actions of LXA 4 on cultured human conjunctival goblet cell mucin secretion and increase in intracellular [Ca 2+ ] ([Ca 2+ ] i ) and on histamine-stimulated responses. LXA 4 increased mucin secretion and [Ca 2+ ] i , and activated ERK1/2 in human goblet cells. Addition of LXA 4 before resolvin D1 (RvD1) decreased RvD1 responses though RvD1 did not block LXA 4 responses. LXA 4 inhibited histamine-stimulated increases in mucin secretion, [Ca 2+ ] i , and ERK1/2 activation through activation of β-adrenergic receptor kinase 1. We conclude that conjunctival goblet cells respond to LXA 4 through the ALX/FPR2 receptor to maintain homeostasis of the ocular surface and regulate histamine responses and could provide a new therapeutic approach for allergic conjunctivitis and dry eye diseases.

Lipoxin A4 Counter-regulates Histamine-stimulated Glycoconjugate Secretion in Conjunctival Goblet Cells

PubMed Central

Hodges, Robin R.; Li, Dayu; Shatos, Marie A.; Serhan, Charles N.; Dartt, Darlene A.

2016-01-01

Conjunctival goblet cells synthesize and secrete mucins which play an important role in protecting the ocular surface. Pro-resolution mediators, such as lipoxin A4 (LXA4), are produced during inflammation returning the tissue to homeostasis and are also produced in non-inflamed tissues. The purpose of this study was to determine the actions of LXA4 on cultured human conjunctival goblet cell mucin secretion and increase in intracellular [Ca2+] ([Ca2+]i) and on histamine-stimulated responses. LXA4 increased mucin secretion and [Ca2+]i, and activated ERK1/2 in human goblet cells. Addition of LXA4 before resolvin D1 (RvD1) decreased RvD1 responses though RvD1 did not block LXA4 responses. LXA4 inhibited histamine-stimulated increases in mucin secretion, [Ca2+]i, and ERK1/2 activation through activation of β-adrenergic receptor kinase 1. We conclude that conjunctival goblet cells respond to LXA4 through the ALX/FPR2 receptor to maintain homeostasis of the ocular surface and regulate histamine responses and could provide a new therapeutic approach for allergic conjunctivitis and dry eye diseases. PMID:27824117

Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun

Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative andmore » anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.« less

Effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with canine herpesvirus-1.

PubMed

Nicklin, Amanda M; McEntee, Margaret C; Ledbetter, Eric C

2014-12-05

Latent canine herpesvirus-1 (CHV-1) infections are common in domestic dogs, but stimuli causing viral reactivation and recrudescent disease are poorly understood. Immunosuppressive pharmaceuticals are currently the only experimentally established triggers for recurrent ocular CHV-1 infection in dogs; however, ocular CHV-1 shedding has been reported clinically following strontium-90 beta radiotherapy of the ocular surface and it has been speculated that radiotherapy can directly induce viral reactivation. Strontium-90 is used as a beta radiation source for the treatment of a variety of neoplastic and immune-mediated canine ocular surface diseases. In the present study, the effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with CHV-1 were evaluated. Ten mature dogs with experimentally induced latent CHV-1 infections were randomly divided into two groups: one group received a single fraction 50 Gy radiation dose in one application from a strontium-90 ophthalmic applicator and the second group received sham radiotherapy. Dogs were then monitored for 45 days for recurrent ocular CHV-1 infection using clinical and virological outcome measures. Clinical ophthalmic examinations, ocular sample CHV-1 PCR assays, and serum CHV-1 virus neutralizing antibody assays were performed at specified intervals. No abnormalities suggestive of recurrent CHV-1 ocular disease were observed on clinical examination in any dog during the study. Ocular viral shedding was not detected and CHV-1 virus neutralizing titers remained stable in all dogs. A single fraction 50 Gy radiation dose administered to the ocular surface by strontium-90 beta radiotherapy did not result in detectable recurrent ocular CHV-1 infection in mature dogs with experimentally induced latent infection. Copyright © 2014 Elsevier B.V. All rights reserved.

The enhancement of biological ocular UV radiation on beaches compared to the radiation on grass.

PubMed

Liu, Guang-Cong; Wang, Fang; Gao, Yan-Yan; Yang, Zheng; Hu, Li-Wen; Gao, Qian; Ri, Jun-Chol; Liu, Yang

2014-12-01

The influence of albedo on ocular UV exposure has seldom been reported. This paper aimed to explore the enhancement effect on measured ocular UV radiation due to a sand surface compared to measured ocular UV radiation due to a grass surface. We measured ambient and ocular UV radiation over the beach and grass surface in Sanya City of China (18.4°N, 109.7°E). The experimental apparatus was composed of a manikin and a dual-detector spectrometer. Integration of both UVA and UVB radiation was used to denote UV radiation. Then biologically effective ocular UVB radiation (UVBE) and the ratios of UVBE of two surfaces were calculated. Maximum of ocular UV radiation versus time over the two surfaces is bimodal. UVBE on the beach is significantly larger than UVBE on the sand, and UVBE peaked at different solar elevation angle (SEA) over the two surfaces (about 53° and 40° on the beach and grass, respectively, according to Bayesian regression). The maximum of ocular UVBE ratios is greater than two, which peaked SEA was about 50°. One hour's cumulative radiation under sunny weather exceeds thresholds for photokeratitis, conjunctivitis and lens damage. Higher albedo significantly increased biological ocular UV radiation. Tourists on tropical beaches should take protective measures and avoid facing the sun directly, especially when SEA is around 50°. Copyright © 2014 Elsevier B.V. All rights reserved.

Multifunctional organic–inorganic hybrid nanoparticles and nanosheets based on chitosan derivative and layered double hydroxide: cellular uptake mechanism and application for topical ocular drug delivery

PubMed Central

Chi, Huibo; Gu, Yan; Xu, Tingting; Cao, Feng

2017-01-01

To study the cellular uptake mechanism of multifunctional organic–inorganic hybrid nanoparticles and nanosheets, new chitosan–glutathione–valine–valine-layered double hydroxide (CG-VV-LDH) nanosheets with active targeting to peptide transporter-1 (PepT-1) were prepared, characterized and further compared with CG-VV-LDH nanoparticles. Both organic–inorganic hybrid nanoparticles and nanosheets showed a sustained release in vitro and prolonged precorneal retention time in vivo, but CG-VV-LDH nanoparticles showed superior permeability in the isolated cornea of rabbits than CG-VV-LDH nanosheets. Furthermore, results of cellular uptake on human corneal epithelial primary cells (HCEpiC) and retinal pigment epithelial (ARPE-19) cells indicated that both clathrin-mediated endocytosis and active transport of PepT-1 are involved in the internalization of CG-VV-LDH nanoparticles and CG-VV-LDH nanosheets. In summary, the CG-VV-LDH nanoparticle may be a promising carrier as a topical ocular drug delivery system for the treatment of ocular diseases of mid-posterior segments, while the CG-VV-LDH nanosheet may be suitable for the treatment of ocular surface diseases. PMID:28280329

Sustained release and permeation of timolol from surface-modified solid lipid nanoparticles through bioengineered human cornea.

PubMed

Attama, A A; Reichl, S; Müller-Goymann, C C

2009-08-01

The aim of the study was to formulate and evaluate surface-modified solid lipid nanoparticles sustained delivery system of timolol hydrogen maleate, a prototype ocular drug using a human cornea construct. Surface-modified solid lipid nanoparticles containing timolol with and without phospholipid were formulated by melt emulsification with high-pressure homogenization and characterized by particle size, wide-angle X-ray diffraction, encapsulation efficiency, and in vitro drug release. Drug transport studies through cornea bioengineered from human donor cornea cells were carried out using a modified Franz diffusion cell and drug concentration analyzed by high-performance liquid chromatography. Results show that surface-modified solid lipid nanoparticles possessed very small particles (42.9 +/- 0.3 nm, 47.2 +/- 0.3 nm, 42.7 +/- 0.7 nm, and 37.7 +/- 0.3 nm, respectively for SM-SLN 1, SM-SLN 2, SM-SLN 3, and SM-SLN 4) with low polydispersity indices, increased encapsulation efficiency (> 44%), and sustained in vitro release compared with unmodified lipid nanoparticles whose particles were greater than 160 nm. Permeation of timolol hydrogen maleate from the surface-modified lipid nanoparticles across the cornea construct was sustained compared with timolol hydrogen maleate solution in distilled water. Surface-modified solid lipid nanoparticles could provide an efficient way of improving ocular bioavailability of timolol hydrogen maleate.

Involvement of p63 in the herpes simplex virus-1-induced demise of corneal cells.

PubMed

Orosz, László; Gallyas, Eva; Kemény, Lajos; Mándi, Yvette; Facskó, Andrea; Megyeri, Klára

2010-06-07

The transcription factor p63 plays a pivotal role in the development and maintenance of epithelial tissues, including the ocular surface. In an effort to gain insight into the pathogenesis of keratitis caused by HSV-1, we determined the expression patterns of the p63 and Bax proteins in the Staatens Seruminstitute Rabbit Cornea cell line (SIRC). SIRC cells were infected with HSV-1 at various multiplicities and maintained for different periods of time. Virus replication was measured by indirect immunofluorescence assay and Western blot analysis. Cell viability was determined by MTT assay. The apoptotic response of the infected cells was quantified by ELISA detecting the enrichment of nucleosomes in the cytoplasm. Western blot analysis was used to determine the levels of p63 and Bax proteins. Indirect immunofluorescence assays and Western blot analyses demonstrated the presence of HSV-1 glycoprotein D (gD) in the infected SIRC cell line, and the pattern of gD expression was consistent with efficient viral replication. The results of MTT and ELISA assays showed that HSV-1 elicited a strong cytopathic effect, and apoptosis played an important role in the demise of the infected cells. Mock-infected SIRC cells displayed the constitutive expression of DeltaNp63alpha. The expressions of the Bax-beta and TAp63gamma isoforms were considerably increased, whereas the level of DeltaNp63alpha was decreased in the HSV-1-infected SIRC cells. Experiments involving the use of acyclovir showed that viral DNA replication was necessary for the accumulation of TAp63gamma. These data suggest that a direct, virus-mediated cytopathic effect may play an important role in the pathogenic mechanism of herpetic keratitis. By disturbing the delicate balance between the pro-survival DeltaN and the pro-apoptotic TA isoforms, HSV-1 may cause profound alterations in the viability of the ocular cells and in the tissue homeostasis of the ocular surface.

Improvement of chronic corneal opacity in ocular surface disease with prosthetic replacement of the ocular surface ecosystem (PROSE) treatment.

PubMed

Cressey, Anna; Jacobs, Deborah S; Remington, Crystal; Carrasquillo, Karen G

2018-06-01

To demonstrate clearing of chronic corneal opacities and improvement of visual acuity with the use of BostonSight prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in ocular surface disease. We undertook retrospective analysis of the medical records of a series of patients who underwent PROSE treatment from August 2006 to December 2014. Patients were referred for ocular surface disease of various etiologies. Primary inclusion criterion was corneal opacity that improved with PROSE treatment. Patients were excluded if topical steroids or adjuvant therapy used once PROSE treatment was initiated. Underlying disease, prior treatment, clinical presentation, and clinical course were extracted from the medical record. Four patients are included in this series. There were three females and one male; median age at time of treatment initiation was 30 years (range = 0.5-58 years). Median duration of PROSE treatment at time of retrospective analysis was 3.5 years (range = 1-8 years). Two cases had corneal opacification in the context of neurotrophic keratopathy: a unilateral case due to presumed herpes simplex keratitis and a bilateral case due to congenital corneal anesthesia associated with familial dysautonomia. One case had corneal opacity from exposure related to seventh nerve palsy, and one had corneal opacification associated with recurrent surface breakdown, neurotrophic keratopathy, and limbal stem deficiency of uncertain etiology. After consistent wear of prosthetic devices used in PROSE treatment for support of the ocular surface, visual acuity improved and clearing of the opacities was observed, without use of topical steroids or adjuvant therapy. These cases demonstrate clearing of chronic corneal opacity with PROSE treatment for ocular surface disease. This clearing can occur with no adjuvant therapy, suggesting that restoration of ocular surface function and integrity allows for corneal remodeling.

Dry Eye Disease and Microbial Keratitis: Is There a Connection?

PubMed Central

Narayanan, Srihari; Redfern, Rachel L.; Miller, William L.; Nichols, Kelly K.; McDermott, Alison M.

2013-01-01

Dry eye is a common ocular surface disease of multifactorial etiology characterized by elevated tear osmolality and inflammation leading to a disrupted ocular surface. The latter is a risk factor for ocular surface infection, yet overt infection is not commonly seen clinically in the typical dry eye patient. This suggests that important innate mechanisms operate to protect the dry eye from invading pathogens. This article reviews the current literature on epidemiology of ocular surface infection in dry eye patients and laboratory-based studies on innate immune mechanisms operating at the ocular surface and their alterations in human dry eye and animal models. The review highlights current understanding of innate immunity in dry eye and identifies gaps in our knowledge to help direct future studies to further unravel the complexities of dry eye disease and its sequelae. PMID:23583043

Tear clearance implications for ocular surface health.

PubMed

de Paiva, Cintia Sade; Pflugfelder, Stephen C

2004-03-01

Tear clearance/turnover provides a global assessment of the function of the lacrimal functional unit and of tear exchange on the ocular surface. It is an indirect measure of dry eye induced inflammation on the ocular surface. It shows better correlation with the severity of ocular irritation symptoms and corneal epithelial disease in dry eye than the Schirmer 1 test. Delayed tear clearance may prove to be the best measure for identifying patients with tear film disorders who may respond to anti-inflammatory therapy.

ELECTRICAL SIGNALING IN CONTROL OF OCULAR CELL BEHAVIORS

PubMed Central

Zhao, Min; Chalmers, Laura; Cao, Lin; Viera, Ana C.; Mannis, Mark; Reid, Brian

2011-01-01

Epithelia of the cornea, lens and retina contain a vast array of ion channels and pumps. Together they produce a polarized flow of ions in and out of cells, as well as across the epithelia. These naturally occurring ion fluxes are essential to the hydration and metabolism of the ocular tissues, especially for the avascular cornea and lens. The directional transport of ions generates electric fields and currents in those tissues. Applied electric fields affect migration, division and proliferation of ocular cells which are important in homeostasis and healing of the ocular tissues. Abnormalities in any of those aspects may underlie many ocular diseases, for example chronic corneal ulcers, posterior capsule opacity after cataract surgery, and retinopathies. Electric field-inducing cellular responses, termed electrical signaling here, therefore may be an unexpected yet powerful mechanism in regulating ocular cell behavior. Both endogenous electric fields and applied electric fields could be exploited to regulate ocular cells. We aim to briefly describe the physiology of the naturally occurring electrical activities in the corneal, lens, and retinal epithelia, to provide experimental evidence of the effects of electric fields on ocular cell behaviors, and to suggest possible clinical implications. PMID:22020127

Coal dust contiguity-induced changes in the concentration of TNF- and NF- B p65 on the ocular surface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Z.Y.; Hong, J.; Liu, Z.Y.

2009-07-01

To observe the influence of coal dust on ocular surface of coal miners and rabbits with coal dust contiguity on expression TNF- and NF- Bp65 and dry eye occurrence. Expression TNF- and NF- Bp65 in ocular surface were determined. Results showed tear production, BUT and lysozyme decreased for coal miners and rabbits with coal dust contiguity. Coal dust exposure was linked to development of xerophthalmia, and induced a higher expression of NF- B p65 and TNF- perhaps as a mechanism to resist coal dust ocular surface injury.

Functional relationship between cationic amino acid transporters and beta-defensins: implications for dry skin diseases and the dry eye.

PubMed

Jäger, Kristin; Garreis, Fabian; Posa, Andreas; Dunse, Matthias; Paulsen, Friedrich P

2010-04-20

The ocular surface, constantly exposed to environmental pathogens, is particularly vulnerable to infection. Hence an advanced immune defence system is essential to protect the eye from microbial attack. Antimicrobial peptides, such as beta-defensins, are essential components of the innate immune system and are the first line of defence against invaders of the eye. High concentrations of L-arginine and L-lysine are necessary for the expression of beta-defensins. These are supplied by epithelial cells in inflammatory processes. The limiting factor for initiation of beta-defensin production is the transport of L-arginine and L-lysine into the cell. This transport is performed to 80% by only one transporter system in the human, the y(+)-transporter. This group of proteins exclusively transports the cationic amino acids L-arginine, L-lysine and L-ornithine and is also known under the term cationic amino acid transporter proteins (CAT-proteins). Various infections associated with L-arginine deficiency (for example psoriasis, keratoconjuctivitis sicca) are also associated with an increase in beta-defensin production. For the first time, preliminary work has shown the expression of human CATs in ocular surface epithelia and tissues of the lacrimal apparatus indicating their relevance for diseases of the ocular surface. In this review, we summarize current knowledge on the human CATs that appear to be integrated in causal regulation cascades of beta-defensins, thereby offering novel concepts for therapeutic perspectives. Copyright 2010 Elsevier GmbH. All rights reserved.

In-vivo expansion of autologous limbal stem cell using simple limbal epithelial transplantation for treatment of limbal stem cell deficiency

PubMed Central

Lal, Ikeda; Panchal, Bhavik Uttam; Basu, Sayan; Sangwan, Virender S

2013-01-01

A 20-year-old man from Bangladesh suffered accidental alkali injury to his right eye in May 2010 leading to total limbal stem cell deficiency. An amniotic membrane graft was performed 5 days after the accident and the patient presented to our institute 6 months later. On ocular examination, his best corrected visual acuity (BCVA) was 20/50 with a 360° pannus at the periphery and central area was spared but had stromal scarring. He underwent simple limbal epithelial transplantation (SLET) taking a limbal biopsy from his left eye and was prescribed steroid and antibiotic eye drops postoperatively as per the standard regimen. At 2 year follow-up, the patient's ocular surface is stable with improvement in  BCVA to 20/25 post-SLET. PMID:23704435

The ocular lesions of naturally occurring lymphocystis in fish.

PubMed Central

Dukes, T W; Lawler, A R

1975-01-01

Six cases of ocular lymphocystis, a virus disease, are described. Lymphocystis is generally known as a benigh, unique, giant cell disease of fishes causing nodules on the skin and fins. It has been studied extensively because of the virus-host cell relationship that results in extreme size and lack of quick cellular destruction or stimulation to neoplasia. Lymphocystis cells were found behind or in one or both eyes and were also found on the cornea or adjacent skin surfaces. A retrobulbar mass produced extreme exophthalmos. Uveal (choroid and iris) masses were present in most cases. Optic nerve involvement was also seen. It is probable that the virus reached the eye by the blood with the resulting masses forming in situ rather than by direct extension from skin lesions. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:1175076

Comparative Toxicity of Preservatives on Immortalized Corneal and Conjunctival Epithelial Cells

PubMed Central

Ahdoot, Michael; Marcus, Edward; Asbell, Penny A.

2009-01-01

Abstract Purpose Nearly all eye drops contain preservatives to decrease contamination. Nonpreservatives such as disodium-ethylene diamine tetra-acetate (EDTA) and phosphate-buffered saline are also regularly added as buffering agents. These components can add to the toxicity of eye drops and cause ocular surface disease. To evaluate the potential toxicity of these common components and their comparative effects on the ocular surface, a tissue culture model utilizing immortalized corneal and conjunctival epithelial cells was utilized. Methods Immortalized human conjunctival and corneal epithelial cells were grown. At confluency, medium was replaced with 100 μL of varying concentrations of preservatives: benzalkonium chloride (BAK), methyl paraben (MP), sodium perborate (SP), chlorobutanol (Cbl), and stabilized thimerosal (Thi); varying concentrations of buffer: EDTA; media (viable control); and formalin (dead control). After 1 h, solutions were replaced with 150 μL of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazonium bromide). After 4 h, solutions decanted, 100 μL of acid isopropanol added, and the optical density determined at 572 nm to evaluate cell viability. Results Conjunctival and corneal cell toxicity was seen with all preservatives. Depending upon concentration, BAK exhibited from 56% to 89% toxicity. In comparison, Cbl exhibited from 50% to 86%, MP from 30% to 76%, SP from 23% to 59%, and Thi from 70% to 95%. EDTA with minimal toxicity (from 6% to 59%) was indistinguishable from SP. Conclusions Generally, the order of decreasing toxicity at the most commonly used concentrations: Thi (0.0025%) > BAK (0.025%) > Cbl (0.25%) > MP (0.01%) > SP (0.0025%) ≈ EDTA (0.01%). Even at low concentration, these agents will cause some degree of ocular tissue damage. PMID:19284328

Pathophysiology of ocular surface squamous neoplasia

PubMed Central

Gichuhi, Stephen; Ohnuma, Shin-ichi; Sagoo, Mandeep S.; Burton, Matthew J.

2014-01-01

The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC → TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photoimmunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. PMID:25447808

Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: a critical appraisal

PubMed Central

Kashima, Tomoyuki; Itakura, Hirotaka; Akiyama, Hideo; Kishi, Shoji

2014-01-01

Rebamipide was initially developed and approved for use in treating gastric ulcers and lesions associated with gastritis. Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. Investigations have confirmed that rebamipide increases corneal and conjunctival mucin-like substances along with improving corneal and conjunctival injury. Clinically, rebamipide ophthalmic suspensions can effectively treat tear deficiency and mucin-caused corneal epithelial damage, and can restore the microstructure responsible for tear stability. Topical rebamipide has also been shown to be effective in treating other ocular surface disorders such as lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion. Rebamipide’s ability to modify epithelial cell function, improve tear stability, and suppress inflammation in the absence of any known major side effects suggest that it may be a beneficial first drug of choice for severe dry eye treatment and other ocular surface disorders. This review summarizes the history and development of this innovative dry eye treatment from its initial use as an effective stomach medication to its current use in the treatment of dry eye in Japan. PMID:24940041

Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: a critical appraisal.

PubMed

Kashima, Tomoyuki; Itakura, Hirotaka; Akiyama, Hideo; Kishi, Shoji

2014-01-01

Rebamipide was initially developed and approved for use in treating gastric ulcers and lesions associated with gastritis. Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. Investigations have confirmed that rebamipide increases corneal and conjunctival mucin-like substances along with improving corneal and conjunctival injury. Clinically, rebamipide ophthalmic suspensions can effectively treat tear deficiency and mucin-caused corneal epithelial damage, and can restore the microstructure responsible for tear stability. Topical rebamipide has also been shown to be effective in treating other ocular surface disorders such as lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion. Rebamipide's ability to modify epithelial cell function, improve tear stability, and suppress inflammation in the absence of any known major side effects suggest that it may be a beneficial first drug of choice for severe dry eye treatment and other ocular surface disorders. This review summarizes the history and development of this innovative dry eye treatment from its initial use as an effective stomach medication to its current use in the treatment of dry eye in Japan.

Confocal microscopy of epithelial and langerhans cells of the cornea in patients using travoprost drops containing two different preservatives.

PubMed

Marsovszky, László; Resch, Miklós D; Visontai, Zsuzsanna; Németh, János

2014-07-01

The recently developed confocal cornea microscopy offers the opportunity to examine pathologies of the cornea and to gain insight into the activity of innate immunity. We aimed to investigate the corneal epithelial and Langerhans cell (LC) densities along with dry eye parameters in primary open-angle glaucoma (POAG) subjects, treated with either of two commercially available travoprost 0.004 % topical medications containing different preservatives. (1: benzalkonium chloride 0.015 % (TravBAK) and 2: polyquaternium-1 (PQ) 0.001 % (TravPQ). Consecutive case series of nineteen POAG patients on TravBAK (mean age: 64.8 ± 13.6 years), nineteen POAG patients on TravPQ (mean age: 66.8 ± 11.3 years) and nineteen age-matched healthy control subjects (63.8 ± 8.2 years). Ocular surface disease index (OSDI), lid parallel conjunctival folds (LIPCOF), Schirmer test (ST) and tear break up time (TBUT) were assessed, and then corneal epithelial and LC densities were investigated with confocal microscopy. Tear production was significantly reduced in both glaucoma patient groups compared to healthy individuals (p < 0.05). TBUT was significantly reduced and epithelial cell densities were significantly greater in patients treated with TravBAK compared to healthy individuals (p < 0.05 for all). LC densities were greater in both glaucoma groups compared to control subjects (p < 0.05 for all). Travoprost therapy may compromise ocular surface. The limited alertness of the corneal immune system found in patients with TravPQ can be considered as indicators of a less disturbed ocular surface and better controlled corneal homeostasis.

Comparison of Topical Application of TSG-6, Cyclosporine, and Prednisolone for Treating Dry Eye.

PubMed

Kim, Yu Jeong; Ryu, Jin Suk; Park, Se Yeon; Lee, Hyun Ju; Ko, Jung Hwa; Kim, Mee Kum; Wee, Won Ryang; Oh, Joo Youn

2016-04-01

To compare the therapeutic effects of topical tumor necrosis factor (TNF)-α-stimulated gene/protein-6 (TSG-6) with those of cyclosporine and prednisolone eye drops in NOD.B10.H2 mice, a model for inflammation-mediated dry eye. The 12-week-old NOD.B10.H2 mice were topically administered recombinant TSG-6 (0.1%) 4 times a day, 0.05% cyclosporine (Restasis) twice a day, or 1% prednisolone (Pred Forte) 4 times a day for 1 week. Aqueous tear production was measured by phenol red thread test, and corneal epithelial damage was observed with lissamine green and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Conjunctival goblet cell number was evaluated with periodic acid-Schiff staining. The levels of inflammatory cytokines were analyzed in the ocular surface (cornea and conjunctiva) and intraorbital gland. The dose-dependent effects of topical TSG-6 (0.001, 0.01, and 0.1%) were tested. Tear production and goblet cell density were significantly increased in all groups receiving TSG-6, cyclosporine, and prednisolone. Corneal epithelial staining was markedly reduced by TSG-6 and cyclosporine but not by prednisolone. In prednisolone-treated eyes, corneal epithelial thickness was decreased, and apoptosis of corneal epithelial cells was increased. The levels of interferon gamma and TNF-α in the ocular surface and intraorbital gland were significantly repressed by TSG-6 and cyclosporine, and prednisolone treatment significantly reduced the level of interferon gamma. The effects of TSG-6 on the ocular surface and tear production were dose dependent. Topical TSG-6 was as effective in inflammation-mediated dry eye as cyclosporine eye drops. Topical prednisolone suppressed inflammation but induced apoptosis in the corneal epithelium.

[Nasal NK/T cell lymphoma with outstanding performance of ocular symptoms].

PubMed

Liu, Lei; Zhao, Yulin; Wang, Jia; Ma, Fei

2012-09-01

To investigate the clinical features and misdiagnosis of nasal NK/T cell lymphoma with outstanding performance in ocular symptoms. Clinical data of 11 patients who had nasal NK/T cell lymphoma with the outstanding performances in ocular symptoms during 2009 to 2011 were retrospectively analyzed. The rate of misdiagnosis in the first diagnosis and first pathological diagnosis were 72.7% and 27.3% respectively. Nasal NK/T cell lymphoma with obvious ocular symptoms developed quickly and had almost special imaging findings. Nasal NK/T cell lymphoma with outstanding performance of ocular symptoms can be easily misdiagnosed. Comprehensive consideration of the clinical features, imaging findings and pathological examination do help to make accurate diagnosis early.

Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Han; Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp; Hijioka, Kuniaki

2009-04-17

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV,more » with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.« less

Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization.

PubMed

Zhang, Han; Sonoda, Koh-Hei; Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro

2009-04-17

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8+ T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8+ T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

Rebamipide increases the mucin-like glycoprotein production in corneal epithelial cells.

PubMed

Takeji, Yasuhiro; Urashima, Hiroki; Aoki, Akihiro; Shinohara, Hisashi

2012-06-01

Dry eye is a multifactorial disease of tears and the ocular surface due to tear deficiency or excessive tear evaporation. Tear film instability is due to a disturbance in ocular surface mucin leading to a dysfunction of mucin, resulting in dry eye. In this study, we examined the effect of rebamipide, an anti-ulcer agent, on glycoconjugate production, as an indicator of mucin-like glycoprotein in cultured corneal epithelial cells. Further, we investigated the effect of rebamipide on the gene expression of membrane-associated mucins. Confluent cultured human corneal epithelial cells were incubated with rebamipide for 24 h. The glycoconjugate content in the supernatant and the cell extracts was measured by wheat germ agglutinin-enzyme-linked lectin assay combined gel-filtration method. In the experiment on mucin gene expression, cultured human corneal epithelial cells were collected at 0, 3, 6, and 12 h after administration of rebamipide. Real-time quantitative polymerase chain reaction was used to analyze the quantity of MUC1, MUC 4, and MUC16 gene expression. Rebamipide significantly increased the glycoconjugate contents in the supernatant and cell extract. In the mucin gene expression in the cells, rebamipide increased MUC1 and MUC4 gene expression, but did not increase MUC16 gene expression. Rebamipide promoted glycoconjugate, which has a property as a mucin-like glycoprotein, in human corneal epithelial cells. The increased production was mediated by MUC1 and MUC4 gene expression.

The Relation of Ocular Surface Irregularity and Visual Disturbance in Early Stage Acanthamoeba Keratitis.

PubMed

Matsumoto, Yukihiro; Kodama, Asako; Goto, Eiki; Kawakita, Tetsuya; Dogru, Murat; Tsubota, Kazuo

2017-01-01

To evaluate the relation between ocular surface irregularity and visual disturbance in early stage Acanthamoeba keratitis (AK). Fifteen patients with culture-proven AK underwent routine ophthalmic examinations, including best-corrected visual acuity (BCVA) measurement, slitlamp biomicroscope examination, and corneal fluorescein dye staining test, in both the eyes. We also evaluated the corneal sensitivity with Cochet-Bonnet esthesiometer, tear functions by Schirmer's test, and ocular surface irregularity by corneal topography and compared the results with the contralateral healthy eyes in this study. The mean logarithm of the minimum angle of resolution BCVA (0.71±0.77) was significantly lower in the eyes with AK (P=0.002). Epithelial disorders were present in all eyes, and radial keratoneuritis in 14 eyes (93.3%). The mean corneal sensitivity (39.3±24.1 mm) was significantly lower in eyes with AK compared with the healthy eyes (P=0.005). The mean Schirmer's test value (22.5±12.0 mm) in eyes with AK was significantly higher compared with the healthy eyes (P=0.01). The ocular surface irregularity indices (the surface regularity index, 2.47±0.42; the surface asymmetry index, 3.24±1.31) were significantly higher in eyes with AK compared with contralateral healthy eyes (P<0.0001 and P<0.0001, respectively). The ocular surface disease in AK is associated with decrease in corneal sensitivity and increase in Schirmer's test value and ocular surface irregularity indices. The visual disturbance in AK may owe not only to corneal haze but also to ocular surface irregularity.

Immune Privilege and Eye-Derived T-Regulatory Cells.

PubMed

Keino, Hiroshi; Horie, Shintaro; Sugita, Sunao

2018-01-01

Certain cellular components of the eye, such as neural retina, are unable to regenerate and replicate after destructive inflammation. Ocular immune privilege provides the eye with immune protection against intraocular inflammation in order to minimize the risk to vision integrity. The eye and immune system use strategies to maintain the ocular immune privilege by regulating the innate and adaptive immune response, which includes immunological ignorance, peripheral tolerance to eye-derived antigens, and intraocular immunosuppressive microenvironment. In this review, we summarize current knowledge regarding the molecular mechanism responsible for the development and maintenance of ocular immune privilege via regulatory T cells (Tregs), which are generated by the anterior chamber-associated immune deviation (ACAID), and ocular resident cells including corneal endothelial (CE) cells, ocular pigment epithelial (PE) cells, and aqueous humor. Furthermore, we examined the therapeutic potential of Tregs generated by RPE cells that express transforming growth factor beta (TGF- β ), cytotoxic T lymphocyte-associated antigen-2 alpha (CTLA-2 α ), and retinoic acid for autoimmune uveoretinitis and evaluated a new strategy using human RPE-induced Tregs for clinical application in inflammatory ocular disease. We believe that a better understanding of the ocular immune privilege associated with Tregs might offer a new approach with regard to therapeutic interventions for ocular autoimmunity.

Surface modification of model hydrogel contact lenses with hyaluronic acid via thiol-ene "click" chemistry for enhancing surface characteristics.

PubMed

Korogiannaki, Myrto; Zhang, Jianfeng; Sheardown, Heather

2017-10-01

Discontinuation of contact lens wear as a result of ocular dryness and discomfort is extremely common; as many as 26% of contact lens wearers discontinue use within the first year. While patients are generally satisfied with conventional hydrogel lenses, improving on-eye comfort continues to remain a goal. Surface modification with a biomimetic, ocular friendly hydrophilic layer of a wetting agent is hypothesized to improve the interfacial interactions of the contact lens with the ocular surface. In this work, the synthesis and characterization of poly(2-hydroxyethyl methacrylate) surfaces grafted with a hydrophilic layer of hyaluronic acid are described. The immobilization reaction involved the covalent attachment of thiolated hyaluronic acid (20 kDa) on acrylated poly(2-hydroxyethyl methacrylate) via nucleophile-initiated Michael addition thiol-ene "click" chemistry. The surface chemistry of the modified surfaces was analyzed by Fourier transform infrared spectroscopy-attenuated total reflectance and X-ray photoelectron spectroscopy. The appearance of N (1s) and S (2p) peaks on the low resolution X-ray photoelectron spectroscopy spectra confirmed successful immobilization of hyaluronic acid. Grafting hyaluronic acid to the poly(2-hydroxyethyl methacrylate) surfaces decreased the contact angle, the dehydration rate, and the amount of nonspecific sorption of lysozyme and albumin in comparison to pristine hydrogel materials, suggesting the development of more wettable surfaces with improved water-retentive and antifouling properties, while maintaining optical transparency (>92%). In vitro testing also showed excellent viability of human corneal epithelial cells with the hyaluronic acid-grafted poly(2-hydroxyethyl methacrylate) surfaces. Hence, surface modification with hyaluronic acid via thiol-ene "click" chemistry could be useful in improving contact lens surface properties, potentially alleviating symptoms of contact lens related dryness and discomfort during wear.

The temperature-sensitive mutants of Toxoplasma gondii and ocular toxoplasmosis.

PubMed

Lu, Fangli; Huang, Shiguang; Kasper, Lloyd H

2009-01-22

The risk of blindness caused by ocular toxoplasmosis supports efforts to improve our understanding for control of this disease. In this study, the involvement of CD8(+), CD4(+), B cell, and IL-10 gene in the immune response of primary ocular infection with the temperature-sensitive mutant (ts-4) of the RH Toxoplasma gondii strain, and in the protective immunity of ocular ts-4 vaccination and challenge with RH strain was investigated in murine models utilizing inbred C57BL/6 mice-deficient in CD4(+), CD8(+), B cells (microMT), or IL-10 gene. Compared to naive mice, all WT and mutant mice had different degree of ocular pathological changes after ts-4 ocular infection, in which both CD8 KO and IL-10 KO mice showed the most severe ocular lesions. Immunized by ts-4 intracameral (i.c.) inoculation, all mutant mice had partially decreased vaccine-induced resistance associated with increased ocular parasite burdens after RH strain challenge. A significant increase of the percentages of B cells and CD8(+) T cells in the draining lymph nodes were observed in WT and IL-10 KO mice after either infection or challenge. The levels of specific anti-toxoplasma IgG in both eye fluid and serum from all the mice were significantly increased after ts-4 i.c. immunization, except microMT mice. These results suggest that the avirulent ts-4 of T. gondii inoculated intracamerally can induce both ocular pathology and ocular protective immunity; CD4(+), CD8(+), B cell, and IL-10 gene are all necessary to the vaccine-induced resistance to ocular challenge by virulent RH strain, in which CD8(+) T cells are the most important component.

Current Anti-Integrin Therapy for Ocular Disease.

PubMed

Gonzalez-Salinas, Roberto; Hernández-Zimbrón, Luis F; Gulias-Cañizo, Rosario; Sánchez-Vela, Mario Alberto; Ochoa-De La Paz, Lenin; Zamora, Ruben; Quiroz-Mercado, Hugo

2017-10-31

The integrin family of cell adhesion molecules mediates homeostasis, signal transduction, and various other interactions between the cell and the extracellular matrix. Integrins are type-1 transmembrane glycoproteins located on the cell surface, widely expressed in leukocytes, which play an important role in the inflammatory pathway. The purpose of this review is to summarize the current state of anti-integrin therapy and to assess ongoing clinical trials in ocular disease. We performed a search on PubMed, CINAHL, and Embase for the published literature available using the MeSH terms: "integrin therapy" and "αLβ2," "α4β1" and "α4β7," "αvβ3," "αvβ5," and "αvβ1" and/or "ophthalmology," and "clinical trials." We used no language restrictions. We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) "integrin," "therapy," or "treatment"; (2) "clinical trials," "ophthalmology," or "ocular." In addition, the analysis included phase 2 and phase 3 clinical trials with a minimal follow-up of six months. Integrin antagonists have shown their capacity to improve signs and symptoms of patients with dry eye disease, age-related macular degeneration, diabetic macular edema, and vitreomacular traction.

The surface activity of purified ocular mucin at the air-liquid interface and interactions with meibomian lipids.

PubMed

Millar, Thomas J; Tragoulias, Sophia T; Anderton, Philip J; Ball, Malcolm S; Miano, Fausto; Dennis, Gary R; Mudgil, Poonam

2006-01-01

Ocular mucins are thought to contribute to the stability of the tear film by reducing surface tension. The purpose of this study was to compare the effect of different mucins and hyaluronic acid (HA) alone and mixed with meibomian lipids on the surface pressure at an air-liquid interface. A Langmuir trough and Wilhelmy balance were used to measure and compare the surface activity of bovine submaxillary gland mucin (BSM), purified BSM, purified bovine ocular mucin and HA, and mixtures of these with meibomian lipids, phosphatidylcholine, and phosphatidylglycerol. Their appearance at the surface of an air-buffer interface was examined using epifluorescence microscopy. Purified ocular mucin had no surface activity even at concentrations that were 100 times more than normally occur in tears. By contrast, commercial BSM caused changes to surface pressure that were concentration dependent. The surface pressure-area profiles showed surface activity with maximum surface pressures of 12.3-22.5 mN/m depending on the concentration. Purified BSM showed no surface activity at low concentrations, whereas higher concentrations reached a maximum surface pressure of 25 mN/m. HA showed no surface activity, at low or high concentrations. Epifluorescence showed that the mucins were located at the air-buffer interface and changed the appearance of lipid films. Purified bovine ocular mucin and HA have no surface activity. However, despite having no surface activity in their own right, ocular mucins are likely to be present at the surface of the tear film, where they cause an increase in surface pressure by causing a compression of the lipids (a reorganization of the lipids) and alter the viscoelastic properties at the surface.

Animal models to assess the therapeutic efficacy of human serum and serum-converted platelet lysates for dry eye syndrome: Seeing is believing.

PubMed

Tseng, Ching-Li; Seghatchian, Jerard; Burnouf, Thierry

2015-08-01

There is much interest in the clinical use of serum-converted human blood or platelet concentrates in regenerative medicine, most specifically for wound healing and tissue repair of soft and hard tissues. The scientific rationale supporting the clinical efficacy of these preparations is based on the expectation that their physiological mixture of natural growth factors can orchestrate cell expansion and differentiation in vivo. However, a lack of standardization and regulatory oversight of these blood materials maintain a perception of uncertainty in the scientific and medical community on the value of these preparations for some clinical indications. More studies are needed to understand the mechanism of action underlying their expected efficacy and standardize their use, and benefit from their biological versatility. One application of serum is as eye drop for treating dry eye syndrome (DES), a multifactorial disease of the ocular surface, which has a prevalence of 15% of more in the population. DES can lead to chronic inflammation of the ocular surface, surface impairment in the cornea and conjunctiva, and, in patients with Sjogren syndrome, result in a disruption of the ocular surface epithelium. Objective experimental assessment of safety and efficacy of serum eye drops can help establish scientific rationale in optimal product composition and use. This can be achieved, first, through cell cultures with relevant cell models, before considering, then, animal studies using DES animal models. Several models have been evaluated and are reported in this concise review. The model we have developed encompasses the use of rabbits, where their eyes are treated with 0.1% benzalkonium chloride (BAC), a common preservative in ophthalmic agents, 3 times daily for 4 weeks. This relatively mild treatment results in moderate DES pathology, with a stable shortage of tear secretion throughout a 7-week study period, which we found suitable for assessing efficacy of serum eye drops. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090.

PubMed

Contreras-Ruiz, Laura; Mir, Fayaz A; Turpie, Bruce; Krauss, Achim H; Masli, Sharmila

2016-02-01

Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of mistletoe combined with carboxymethyl cellulose on dry eye in postmenopausal women

PubMed Central

Jiang, Nan; Ye, Lin-Hong; Ye, Lei; Yu, Jing; Yang, Qi-Chen; Yuan, Qing; Zhu, Pei-Wen; Shao, Yi

2017-01-01

AIM To investigate the protective effect of mistletoe combined with carboxymethyl cellulose eye drops on dry eye in postmenopausal women. METHODS Sixty postmenopause female patients diagnosed of dry eye were assigned randomly to mistletoe combined with carboxymethyl cellulose eye drops treatment group (n=30) and control group treated with normal saline eye drops (n=30). The subjective symptoms of ocular surface, Ocular Surface Disease Index (OSDI), tear film function tests, tear protein and corneal morphology by confocal scanning microscopy were analyzed before treatment and at 1, 2, 4 and 8wk after treatment respectively. To ensure the safety of the trial, all patients were examined with systolic pressure, diastolic pressure, glutamic-pyruvic transaminase, glutamic oxaloacetic transaminase, urine creatinine, and blood urea nitrogen at 8wk after treatment. RESULTS There were no obvious differences between two groups before the treatment (P>0.05). In two months after the treatment, the symptoms of ocular surface, OSDI, tear protein, and tear film function were only slightly changed in normal saline eye drops group. However, all indices were improved after the treatment of mistletoe combined with carboxymethyl cellulose eye drops group (P<0.05). In addition, the average amount of corneal epithelium basal cells and inflammatory cells of mistletoe treated group were 3174±379 and 38±25 cells/mm2, significantly decreased as compared to the control group with 4309±612 and 158± 61 cells/mm2, respectively. In the control group, although nerves still maintained straight under corneal epithelium, the number of nerves were significantly decreased, as compared with normal female. In the mistletoe treated group, the number of nerves was only slightly reduced, compared with normal female. CONCLUSION Mistletoe combined with carboxymethyl cellulose eye drops can alleviate the symptoms and signs of dry eye symptoms. PMID:29181309

Implications for Ophthalmic Formulations: Ocular Buffers Show Varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells.

PubMed

Schuerer, Nadine; Stein, Elisabeth; Inic-Kanada, Aleksandra; Pucher, Marion; Hohenadl, Christine; Bintner, Nora; Ghasemian, Ehsan; Montanaro, Jacqueline; Barisani-Asenbauer, Talin

2017-06-01

To investigate toxicity associated with buffers commonly used in topical ocular drug formulations using a human corneal-limbal epithelial (HCLE) and a human conjunctival epithelial (HCjE) cell model. HCLE and HCjE cells were incubated for 10, 30, or 60 minutes with 4 different buffers based on borate, citrate, phosphate, and Tris-HCl at 10, 50, and 100 mM concentrations. To detect possible delayed effects on cell viability, after 60 minutes of buffer incubation, cells were further incubated for 24 hours with a cell medium. Cell viability was determined using a colorimetric XTT-based assay. The morphology of cells was also investigated. HCjE cells showed more sensitivity to buffer incubation than HCLE cells. The 100 mM phosphate buffer displayed significant delayed effects on cell viability of HCLE 16.8 ± 4.8% and HCjE 39.2 ± 6.1% cells after 60 minutes of exposure (P < 0.05). HCjE cell viability was reduced after 60 minutes incubations with 50 and 100 mM citrate buffer to 42.8 ± 6.5% and 39.3 ± 7.9%, respectively, and even lower percentages at the delayed time point (both P < 0.05). HCLE cell morphology was distinctly altered by 100 mM phosphate and Tris buffers after 30 minutes, whereas HCjE cells already showed marked changes after 10 minutes of exposure to 100 mM citrate and phosphate buffers. We observed a time-dependent decrease of viability in both HCLE and HCjE cells exposed to higher buffer concentrations. Therefore, we propose further in vivo studies to translate these finding to humans to discern the real effects of the buffer concentration in eye drops on the ocular surface.

Implications for Ophthalmic Formulations: Ocular Buffers Show Varied Cytotoxic Impact on Human Corneal–Limbal and Human Conjunctival Epithelial Cells

PubMed Central

Schuerer, Nadine; Stein, Elisabeth; Inic-Kanada, Aleksandra; Pucher, Marion; Hohenadl, Christine; Bintner, Nora; Ghasemian, Ehsan; Montanaro, Jacqueline

2017-01-01

Purpose: To investigate toxicity associated with buffers commonly used in topical ocular drug formulations using a human corneal–limbal epithelial (HCLE) and a human conjunctival epithelial (HCjE) cell model. Methods: HCLE and HCjE cells were incubated for 10, 30, or 60 minutes with 4 different buffers based on borate, citrate, phosphate, and Tris-HCl at 10, 50, and 100 mM concentrations. To detect possible delayed effects on cell viability, after 60 minutes of buffer incubation, cells were further incubated for 24 hours with a cell medium. Cell viability was determined using a colorimetric XTT–based assay. The morphology of cells was also investigated. Results: HCjE cells showed more sensitivity to buffer incubation than HCLE cells. The 100 mM phosphate buffer displayed significant delayed effects on cell viability of HCLE 16.8 ± 4.8% and HCjE 39.2 ± 6.1% cells after 60 minutes of exposure (P < 0.05). HCjE cell viability was reduced after 60 minutes incubations with 50 and 100 mM citrate buffer to 42.8 ± 6.5% and 39.3 ± 7.9%, respectively, and even lower percentages at the delayed time point (both P < 0.05). HCLE cell morphology was distinctly altered by 100 mM phosphate and Tris buffers after 30 minutes, whereas HCjE cells already showed marked changes after 10 minutes of exposure to 100 mM citrate and phosphate buffers. Conclusions: We observed a time-dependent decrease of viability in both HCLE and HCjE cells exposed to higher buffer concentrations. Therefore, we propose further in vivo studies to translate these finding to humans to discern the real effects of the buffer concentration in eye drops on the ocular surface. PMID:28399036

Mediators and mechanisms of herpes simplex virus entry into ocular cells.

PubMed

Farooq, Asim V; Valyi-Nagy, Tibor; Shukla, Deepak

2010-06-01

The entry of herpes simplex virus into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of herpes simplex virus into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis, and other ocular diseases.

Mediators and Mechanisms of Herpes Simplex Virus Entry into Ocular Cells

PubMed Central

Farooq, Asim V.; Valyi-Nagy, Tibor; Shukla, Deepak

2010-01-01

The entry of herpes simplex virus (HSV) into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of HSV into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis and other ocular diseases. PMID:20465436

Targeted delivery of hyaluronic acid to the ocular surface by a polymer-peptide conjugate system for dry eye disease.

PubMed

Lee, David; Lu, Qiaozhi; Sommerfeld, Sven D; Chan, Amanda; Menon, Nikhil G; Schmidt, Tannin A; Elisseeff, Jennifer H; Singh, Anirudha

2017-06-01

Hyaluronic acid (HA) solutions effectively lubricate the ocular surface and are used for the relief of dry eye related symptoms. However, HA undergoes rapid clearance due to limited adhesion, which necessitates frequent instillation. Conversely, highly viscous artificial tear formulations with HA blur vision and interfere with blinking. Here, we developed an HA-eye drop formulation that selectively binds and retains HA for extended periods of time on the ocular surface. We synthesized a heterobifunctional polymer-peptide system with one end binding HA while the other end binding either sialic acid-containing glycosylated transmembrane molecules on the ocular surface epithelium, or type I collagen molecule within the tissue matrix. HA solution was mixed with the polymer-peptide system and tested on both ex vivo and in vivo models to determine its ability to prolong HA retention. Furthermore, rabbit ocular surface tissues treated with binding peptides and HA solutions demonstrated superior lubrication with reduced kinetic friction coefficients compared to tissues treated with conventional HA solution. The results suggest that binding peptide-based solution can keep the ocular surface enriched with HA for prolonged times as well as keep it lubricated. Therefore, this system can be further developed into a more effective treatment for dry eye patients than a standard HA eye drop. Eye drop formulations containing HA are widely used to lubricate the ocular surface and relieve dry eye related symptoms, however its low residence time remains a challenge. We designed a polymer-peptide system for the targeted delivery of HA to the ocular surface using sialic acid or type I collagen as anchors for HA immobilization. The addition of the polymer-peptide system to HA eye drop exhibited a reduced friction coefficient, and it can keep the ocular surface enriched with HA for prolonged time. This system can be further developed into a more effective treatment for dry eye than a standard HA eye drop. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Microscopic and spectroscopic evaluation of novel PLGA-chitosan Nanoplexes as an ocular delivery system.

PubMed

Jain, Gaurav K; Pathan, Shadab A; Akhter, Sohail; Jayabalan, Nirmal; Talegaonkar, Sushma; Khar, Roop K; Ahmad, Farhan J

2011-02-01

The interaction of PLGA-chitosan Nanoplexes with ocular mucosa was investigated ex vivo and in vivo to assess their potential as ocular delivery system. Fluorescent Rhodamine Nanoplexes (Rd-Nanoplexes) were prepared by ionotropic gelation method. The size and morphology of Nanoplexes was investigated by TEM, SEM and PCS. The corneal retention, uptake and penetration of Nanoplexes were analyzed by spectrofluorimetry and confocal microscopy. Corneas from Rd-Nanoplexes-treated rabbits were evaluated for the in vivo uptake and ocular tolerance. The Nanoplexes prepared were round with a mean diameter of 115.6±17nm and the encapsulation efficiency of Rd was 59.4±2.5%. Data from ex vivo and in vivo studies showed that the amounts of Rd in the cornea were significantly higher for Nanoplexes than for a control Rd solution, these amounts being fairly constant for up to 24h. Confocal microscopy of the corneas revealed paracellular and transcellular uptake of the Nanoplexes. The uptake mechanism postulated was adsorptive-mediated endocytosis and opening of the tight junctions between epithelial cells. No alteration was microscopically observed after ocular surface exposure to Nanoplexes. Taken together, these data demonstrate that Nanoplexes are potentially useful as ocular drug carriers. Copyright © 2010 Elsevier B.V. All rights reserved.

Aniridia and Brachmann-de Lange syndrome: a review of ocular surface and anterior segment findings.

PubMed

Lee, W Barry; Brandt, James D; Mannis, Mark J; Huang, Charles Q; Rabin, Gregory J

2003-03-01

To review the ocular surface and anterior segment findings in Brachmann-de Lange syndrome and describe a new case involving aniridia and congenital glaucoma. A newborn presented 2 days after birth with bilateral cloudy corneas, photophobia, and epiphora. We provide a 5-year descriptive history and clinical course with review of the literature on Brachmann-de Lange syndrome. Multiple ocular surgeries were performed for ocular sequelae from aniridia and congenital glaucoma including Ahmed valve placement and penetrating keratoplasties in both eyes. At 5.5 years of age, the child had a clear graft OD and amblyopia from graft failure OS following recurrent graft infections. A review of Brachmann-de Lange syndrome found 43 patients with ocular surface and anterior segment findings. The most common findings included conjunctivitis, blepharitis, microcornea, and corectopia. Aniridia and congenital glaucoma were not previously reported with Brachmann-de Lange syndrome. Ocular surface and anterior segment abnormalities must be considered when examining patients with Brachmann-de Lange syndrome. Ocular findings may include vision-threatening anomalies, as in our case with aniridia and congenital glaucoma. To our knowledge, these findings are previously unreported in Brachmann-de Lange syndrome.

Dry eye disease: an immune-mediated ocular surface disorder

PubMed Central

Stevenson, William; Chauhan, Sunil K.; Dana, Reza

2013-01-01

Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management. PMID:22232476

Accounting for Ethnicity-Related Differences in Ocular Surface Integrity as a Step Toward Understanding Contact Lens Discomfort.

PubMed

Chan, Stefanie M; Svitova, Tatyana F; Lin, Meng C

2017-01-01

Contact lens discomfort is a common problem that can lead to unsuccessful or limited contact lens wear. Although many factors may contribute to contact lens discomfort, limited research has explored the influence of ethnicity-related differences in the anatomy and physiology of the ocular surface. Therefore, we performed a search of the literature in PubMed using key words related to "ocular surface" paired with the terms "race" and "ethnicity." The goal of this review was to determine potential areas of research regarding ethnicity differences, particularly between Asian and non-Asian eyes, in ocular surface integrity to advance our understanding of contact lens discomfort.

A mouse dry eye model induced by topical administration of benzalkonium chloride.

PubMed

Lin, Zhirong; Liu, Xiaochen; Zhou, Tong; Wang, Yihui; Bai, Li; He, Hui; Liu, Zuguo

2011-01-25

To develop a dry eye model of mouse induced by topical administration of benzalkonium chloride (BAC) and investigate the possible mechanisms. BAC at concentration of 0.2% was applied to the mouse ocular surface for 7 days. Phenol red thread tear test, tear break-up time (BUT) test, corneal inflammatory index scoring, fluorescein and rose bengal test were performed to evaluate the toxic effects of BAC on the ocular surface. Global specimens were collected on day (D) 7 and labeled with a series of antibodies including cytokeratin 10 (K10) and mucin 5AC (MUC5AC). Apoptosis of ocular surface epithelium was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Histologic analysis and transmission electron microscopy (TEM) were performed on D7. BAC at a concentration of 0.2% successfully induced a dry eye condition with decreased tear volume and BUTs, increased corneal fluorescein and rose bengal scores. The Inflammatory index was increased in accompaniment with higher tumor necrosis factor-α (TNF-α) expression and more inflammatory infiltration in the cornea. Immunolabeling revealed positive K10 expression in BAC-treated corneal epithelium and fewer MUC5AC-positive cells in the BAC-treated conjunctival fornix. TUNEL assay showed more apoptotic cells in the corneal basal epithelium. TEM showed that the size and intervals of the microvillis were both reduced in the corneal epithelium. Topical administration of 0.2% BAC in mouse induces changes resembling that of dry eye syndrome in humans, and thus, represents a novel model of dry eye.

A mouse dry eye model induced by topical administration of benzalkonium chloride

PubMed Central

Lin, Zhirong; Liu, Xiaochen; Zhou, Tong; Wang, Yihui; Bai, Li; He, Hui

2011-01-01

Purpose To develop a dry eye model of mouse induced by topical administration of benzalkonium chloride (BAC) and investigate the possible mechanisms. Methods BAC at concentration of 0.2% was applied to the mouse ocular surface for 7 days. Phenol red thread tear test, tear break-up time (BUT) test, corneal inflammatory index scoring, fluorescein and rose bengal test were performed to evaluate the toxic effects of BAC on the ocular surface. Global specimens were collected on day (D) 7 and labeled with a series of antibodies including cytokeratin 10 (K10) and mucin 5AC (MUC5AC). Apoptosis of ocular surface epithelium was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Histologic analysis and transmission electron microscopy (TEM) were performed on D7. Results BAC at a concentration of 0.2% successfully induced a dry eye condition with decreased tear volume and BUTs, increased corneal fluorescein and rose bengal scores. The Inflammatory index was increased in accompanyment with higher tumor necrosis factor-α (TNF-α) expression and more inflammatory infiltration in the cornea. Immunolabeling revealed positive K10 expression in BAC-treated corneal epithelium and fewer MUC5AC-positive cells in the BAC-treated conjunctival fornix. TUNEL assay showed more apoptotic cells in the corneal basal epithelium. TEM showed that the size and intervals of the microvillis were both reduced in the corneal epithelium. Conclusions Topical administration of 0.2% BAC in mouse induces changes resembling that of dry eye syndrome in humans, and thus, represents a novel model of dry eye. PMID:21283525

Effect of Omega-3 Fatty Acids Dietary Supplementation on Ocular Surface and Tear Film in Diabetic Patients with Dry Eye.

PubMed

Georgakopoulos, Constantine D; Makri, Olga E; Pagoulatos, Dionisios; Vasilakis, Panagiotis; Peristeropoulou, Politimi; Kouli, Vasiliki; Eliopoulou, Maria I; Psachoulia, Caterina

2017-01-01

The objective of this study was to investigate the effect of dietary supplementation with omega-3 fatty acids on ocular surface and tear film in patients with type 2 diabetes suffering from dry eye. Thirty-six patients suffering from type 2 diabetes and moderate to severe dry eye syndrome were included in the study. Patients were assigned to receive omega-3 long-chain polyunsaturated fatty acids for 3 months. Tear film break-up time test, Schirmer-I test, and conjunctival impression cytology analysis were performed on all patients at baseline and after 1 and 3 months. The subjective symptoms of dry eye were evaluated with the Ocular Surface Disease Index (OSDI) questionnaire at the same time points. Patients' average age was 65.57 ± 4.27 years and the mean duration of diabetes was 14.85 ± 5.4 years. There was a statistically significant increase in Schirmer-I test results and tear break-up time score after 3 months of supplementary intake of omega-3 fatty acids compared to baseline (p < 0.05 and p < 0.001, respectively). Impression cytology demonstrated a significantly lower grade of conjunctival squamous cell metaplasia after 1 and 3 months of omega-3 fatty acids intake compared to baseline (p < 0.05 and p < 0.01, respectively). The OSDI score was statistically significant lower both at 1 and 3 months after omega-3 fatty acids supplementation compared to baseline (p < 0.001). Omega-3 fatty acids may effectively improve tear film characteristics, reverse ocular surface features, and alleviate the subjective symptoms associated with dry eye syndrome in patients with type 2 diabetes.

Interfacial Interaction between Transmembrane Ocular Mucins and Adhesive Polymers and Dendrimers Analyzed by Surface Plasmon Resonance

PubMed Central

Noiray, M.; Briand, E.; Woodward, A. M.; Argüeso, P.; Molina Martínez, I. T.; Herrero-Vanrell, R.; Ponchel, G.

2013-01-01

Purpose Development of the first in vitro method based on biosensor chip technology designed for probing the interfacial interaction phenomena between transmembrane ocular mucins and adhesive polymers and dendrimers intended for ophthalmic administration. Methods The surface plasmon resonance (SPR) technique was used. A transmembrane ocular mucin surface was prepared on the chip surface and characterized by QCM-D (Quartz Crystal Microbalance with Dissipation) and XPS (X-ray photoelectron spectroscopy). The mucoadhesive molecules tested were: hyaluronic acid (HA), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), chitosan (Ch) and polyamidoamine dendrimers (PAMAM). Results While Ch originated interfacial interaction with ocular transmembrane mucins, for HA, CMC and HPMC, chain interdiffusion seemed to be mandatory for bioadherence at the concentrations used in ophthalmic clinical practise. Interestingly, PAMAM dendrimers developed permanent interfacial interactions with transmembrane ocular mucins whatever their surface chemical groups, showing a relevant importance of co-operative effect of these multivalent systems. Polymers developed interfacial interactions with ocular membrane-associated mucins in the following order: Ch(1 %) > G4PAMAM-NH2(2 %) = G4PAMAM-OH(2 %) > G3.5PAMAM-COOH(2 %)≫ CMC(0.5 %) = HA(0.2 %) = HPMC(0.3 %). Conclusions The method proposed is useful to discern between the mucin-polymer chemical interactions at molecular scale. Results reinforce the usefulness of chitosan and den-drimers as polymers able to increase the retention time of drugs on the ocular surface and hence their bioavailability. PMID:22565639

Ophthalmic Manifestations of Xeroderma Pigmentosum: A Perspective from the United Kingdom.

PubMed

Lim, Rongxuan; Sethi, Mieran; Morley, Ana M S

2017-11-01

To document the ocular manifestations of xeroderma pigmentosum (XP), presenting via the United Kingdom (UK) XP service, and to analyze the correlations between XP genotype and ophthalmic phenotype. Prospective observational case series. Eighty-nine patients seen by the UK Nationally Commissioned XP Service, from April 2010 to December 2014, with a genetically confirmed diagnosis of XP. Patients underwent a full ophthalmic examination at each visit. Clinical features from both eyes were recorded on a standard proforma. The most recent assessments were analyzed. A 2-tailed Fisher exact test was used to assess for differences in ocular features between patients in XP subgroups with impaired transcription coupled nucleotide excision repair (TC-NER) (category 1: XP-A, B, D, F, and G) and preserved TC-NER (category 2: XP-C, E, and V). Lid and periocular abnormalities, ocular surface pathologies, neuro-ophthalmologic abnormalities, lens and retinal abnormalities, and visual acuity (VA). Ninety-three percent of XP patients in our cohort had ocular involvement, with 65% describing photophobia. The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). Eleven percent of patients had required treatment for periocular cancers and 2% for ocular surface cancers. The most common neuro-ophthalmologic finding was minimal pupillary reaction to light (25%). Patients in category 2 had significantly more ocular surface abnormalities than patients in category 1, including a greater proportion of conjunctival injection (P = 0.003), conjunctival corkscrew vessels (P < 0.001), corneal scarring (P = 0.01) and pingueculae under the age of 50 (P = 0.02). Meanwhile, patients in category 1 had a higher proportion of poorly reactive pupils (P < 0.001) and abnormal ocular movements (P = 0.03) compared with those in category 2. Five patients (6%) presented to ophthalmologists with ocular surface signs related to XP, before any formal diagnosis of XP was made. A large proportion of XP patients have ocular involvement. Regular examination by an ophthalmologist is essential, especially in screening for eyelid and ocular surface tumors. The ocular phenotype-genotype segregation within XP patients suggests that XP is a heterogeneous and complex disease. With further study, we hope to offer these patients more individualized patient care. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The ocular surface and tear film and their dysfunction in dry eye disease.

PubMed

Rolando, M; Zierhut, M

2001-03-01

The ocular surface, tear film, lacrimal glands, and eyelids act as a functional unit to preserve the quality of the refractive surface of the eye and to resist injury and protect the eye against changing bodily and environmental conditions. Events that disturb the homeostasis of this functional unit can result in a vicious cycle of ocular surface disease. The tear film is the most dynamic structure of the functional unit, and its production and turnover is essential to maintaining the health of the ocular surface. Classically, the tear film is reported to be composed of three layers: the mucin, aqueous, and lipid layers. The boundaries and real thickness of such layers is still under discussion. A dysfunction of any of these layers can result in dry eye disease.

Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice

PubMed Central

Wang, Changjun; Zaheer, Mahira; Bian, Fang; Quach, Darin; Swennes, Alton G.; Britton, Robert A.; Pflugfelder, Stephen C.

2018-01-01

Commensal bacteria play an important role in the formation of the immune system but their role in the maintenance of immune homeostasis at the ocular surface and lacrimal gland remains poorly understood. This study investigated the eye and lacrimal gland phenotype in germ-free and conventional C57BL/6J mice. Our results showed that germ-free mice had significantly greater corneal barrier disruption, greater goblet cell loss, and greater total inflammatory cell and CD4+ T cell infiltration within the lacrimal gland compared to the conventionally housed group. A greater frequency of CD4+IFN-γ+ cells was observed in germ-free lacrimal glands. Females exhibited a more severe phenotype compared to males. Adoptive transfer of CD4+ T cells isolated from female germ-free mice into RAG1KO mice transferred Sjögren-like lacrimal keratoconjunctivitis. Fecal microbiota transplant from conventional mice reverted dry eye phenotype in germ-free mice and decreased CD4+IFN-γ+ cells to levels similar to conventional C57BL/6J mice. These findings indicate that germ-free mice have a spontaneous lacrimal keratoconjunctivitis similar to that observed in Sjögren syndrome patients and demonstrate that commensal bacteria function in maintaining immune homeostasis on the ocular surface. Thus, manipulation of intestinal commensal bacteria has the potential to become a novel therapeutic approach to treat Sjögren Syndrome. PMID:29438346

A new safety concern for glaucoma treatment demonstrated by mass spectrometry imaging of benzalkonium chloride distribution in the eye, an experimental study in rabbits.

PubMed

Brignole-Baudouin, Françoise; Desbenoit, Nicolas; Hamm, Gregory; Liang, Hong; Both, Jean-Pierre; Brunelle, Alain; Fournier, Isabelle; Guerineau, Vincent; Legouffe, Raphael; Stauber, Jonathan; Touboul, David; Wisztorski, Maxence; Salzet, Michel; Laprevote, Olivier; Baudouin, Christophe

2012-01-01

We investigated in a rabbit model, the eye distribution of topically instilled benzalkonium_(BAK) chloride a commonly used preservative in eye drops using mass spectrometry imaging. Three groups of three New Zealand rabbits each were used: a control one without instillation, one receiving 0.01%BAK twice a day for 5 months and one with 0.2%BAK one drop a day for 1 month. After sacrifice, eyes were embedded and frozen in tragacanth gum. Serial cryosections were alternately deposited on glass slides for histological (hematoxylin-eosin staining) and immunohistological controls (CD45, RLA-DR and vimentin for inflammatory cell infiltration as well as vimentin for Müller glial cell activation) and ITO or stainless steel plates for MSI experiments using Matrix-assisted laser desorption ionization time-of-flight. The MSI results were confirmed by a round-robin study on several adjacent sections conducted in two different laboratories using different sample preparation methods, mass spectrometers and data analysis softwares. BAK was shown to penetrate healthy eyes even after a short duration and was not only detected on the ocular surface structures, but also in deeper tissues, especially in sensitive areas involved in glaucoma pathophysiology, such as the trabecular meshwork and the optic nerve areas, as confirmed by images with histological stainings. CD45-, RLA-DR- and vimentin-positive cells increased in treated eyes. Vimentin was found only in the inner layer of retina in normal eyes and increased in all retinal layers in treated eyes, confirming an activation response to a cell stress. This ocular toxicological study confirms the presence of BAK preservative in ocular surface structures as well as in deeper structures involved in glaucoma disease. The inflammatory cell infiltration and Müller glial cell activation confirmed the deleterious effect of BAK. Although these results were obtained in animals, they highlight the importance of the safety-first principle for the treatment of glaucoma patients.

A New Safety Concern for Glaucoma Treatment Demonstrated by Mass Spectrometry Imaging of Benzalkonium Chloride Distribution in the Eye, an Experimental Study in Rabbits

PubMed Central

Brignole-Baudouin, Françoise; Desbenoit, Nicolas; Hamm, Gregory; Liang, Hong; Both, Jean-Pierre; Brunelle, Alain; Fournier, Isabelle; Guerineau, Vincent; Legouffe, Raphael; Stauber, Jonathan; Touboul, David; Wisztorski, Maxence; Salzet, Michel; Laprevote, Olivier; Baudouin, Christophe

2012-01-01

We investigated in a rabbit model, the eye distribution of topically instilled benzalkonium_(BAK) chloride a commonly used preservative in eye drops using mass spectrometry imaging. Three groups of three New Zealand rabbits each were used: a control one without instillation, one receiving 0.01%BAK twice a day for 5 months and one with 0.2%BAK one drop a day for 1 month. After sacrifice, eyes were embedded and frozen in tragacanth gum. Serial cryosections were alternately deposited on glass slides for histological (hematoxylin-eosin staining) and immunohistological controls (CD45, RLA-DR and vimentin for inflammatory cell infiltration as well as vimentin for Müller glial cell activation) and ITO or stainless steel plates for MSI experiments using Matrix-assisted laser desorption ionization time-of-flight. The MSI results were confirmed by a round-robin study on several adjacent sections conducted in two different laboratories using different sample preparation methods, mass spectrometers and data analysis softwares. BAK was shown to penetrate healthy eyes even after a short duration and was not only detected on the ocular surface structures, but also in deeper tissues, especially in sensitive areas involved in glaucoma pathophysiology, such as the trabecular meshwork and the optic nerve areas, as confirmed by images with histological stainings. CD45-, RLA-DR- and vimentin-positive cells increased in treated eyes. Vimentin was found only in the inner layer of retina in normal eyes and increased in all retinal layers in treated eyes, confirming an activation response to a cell stress. This ocular toxicological study confirms the presence of BAK preservative in ocular surface structures as well as in deeper structures involved in glaucoma disease. The inflammatory cell infiltration and Müller glial cell activation confirmed the deleterious effect of BAK. Although these results were obtained in animals, they highlight the importance of the safety-first principle for the treatment of glaucoma patients. PMID:23209668

Protecting the ocular surface and improving the quality of life of dry eye patients: a study of the efficacy of an HP-guar containing ocular lubricant in a population of dry eye patients.

PubMed

Rolando, Maurizio; Autori, Silvia; Badino, Francesco; Barabino, Stefano

2009-06-01

The aim of this study was to evaluate the efficacy of a non-Newtonian tear substitute containing 0.4% polyethylene glycol 400 (PEG 400) and 0.3% propylene glycol in an 0.18% hydroxypropyl-guar (HPG) containing vehicle (Systane Lubricant Eye Drops; Alcon) in reducing the signs and symptoms of dry eye, as well as its effect on ocular protection. Twenty patients with moderate to severe dry eye were enrolled in a 28-day prospective, randomized, controlled study. Subjects self-administered the HPG containing ocular lubricant four times daily (QID) over the study duration. After 28 days, the effect of the HPG containing ocular lubricant was evaluated by means of the Global Staining Score (a measure of the corneal and conjunctival staining), inter-blink tear film stability, Ocular Protection Index (OPI), and subjective symptoms. The HPG containing ocular lubricant produced statistically significant improvements compared with baseline in dry eye symptoms (P < 0.0001 at Days 7, 14, and 28); in ocular surface staining, as measured by a reduction in the Global Staining Score (P < 0.0001 at Days 7, 14, and 28); and in the OPI (P = 0.0025 at Day 14 and P = 0.0067 at Day 28). The improvements in ocular surface staining and dry eye symptoms with the HPG containing ocular lubricant -- evident as early as the first follow-up visit (Day 7) and continued throughout the 28 days of the study with a concurrent, increase in OPI to a level greater than unity -- indicate that this preparation is a fast-acting, long-lasting, and effective treatment for dry eye. In concurrence with the results from previously published clinical studies, the HPG containing ocular lubricant has shown efficacy in alleviating the signs and symptoms of dry eye as well as affording improved ocular surface protection.

Oral antioxidant therapy for marginal dry eye.

PubMed

Blades, K J; Patel, S; Aidoo, K E

2001-07-01

To assess the efficacy of an orally administered antioxidant dietary supplement for managing marginal dry eye. A prospective, randomised, placebo controlled trial with cross-over. Eye Clinic, Department of Vision Sciences, Glasgow Caledonian University. Forty marginal dry eye sufferers composed of 30 females and 10 males (median age 53 y; range 38-69 y). Baseline assessments were made of tear volume sufficiency (thread test), tear quality (stability), ocular surface status (conjunctival impression cytology) and dry eye symptoms (questionnaire). Each subject was administered courses of active treatment, placebo and no treatment, in random order for 1 month each and results compared to baseline. Tear stability and ocular surface status were significantly improved following active treatment (P<0.05). No changes from baseline were detected following administration of placebo and no treatment (P>0.05). Absolute increase in tear stability correlated with absolute change in goblet cell population density. Tear volume was not improved following any treatment period and dry eye symptom responses were subject to placebo effect. Oral antioxidants improved both tear stability and conjunctival health, although it is not yet understood whether increased ocular surface health mediates increased tear stability or vice versa. This study was supported by a PhD scholarship funded by the Department of Vision Sciences, Glasgow Caledonian University, Scotland. Antioxidant supplements and placebos were kindly donated by Vitabiotics.

MK2 inhibitor reduces alkali burn-induced inflammation in rat cornea

PubMed Central

Chen, Yanfeng; Yang, Wenzhao; Zhang, Xiaobo; Yang, Shu; Peng, Gao; Wu, Ting; Zhou, Yueping; Huang, Caihong; Reinach, Peter S.; Li, Wei; Liu, Zuguo

2016-01-01

MK2 activation by p38 MAPK selectively induces inflammation in various diseases. We determined if a MK2 inhibitor (MK2i), improves cornea wound healing by inhibiting inflammation caused by burning rat corneas with alkali. Our study, for the first time, demonstrated that MK2i inhibited alkali burn-induced MK2 activation as well as rises in inflammation based on: a) blunting rises in inflammatory index, inflammatory cell infiltration, ED1+ macrophage and PMN+ neutrophil infiltration; b) suppressing IL-6 and IL-1β gene expression along with those of macrophage inflammatory protein-1α (MIP-1α), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1); c) reducing angiogenic gene expression levels and neovascularization (NV) whereas anti-angiogenic PEDF levels increased. In addition, this study found that MK2i did not affect human corneal epithelial cell (HCEC) proliferation and migration and had no detectable side effects on ocular surface integrity. Taken together, MK2i selectively inhibited alkali burn-induced corneal inflammation by blocking MK2 activation, these effects have clinical relevance in the treatment of inflammation related ocular surface diseases. PMID:27329698

The Relationship Between Ocular Itch, Ocular Pain, and Dry Eye Symptoms (An American Ophthalmological Society Thesis).

PubMed

Galor, Anat; Small, Leslie; Feuer, William; Levitt, Roy C; Sarantopoulos, Konstantinos D; Yosipovitch, Gil

2017-08-01

To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs. A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch. The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate-severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate-severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms. Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity.

The Relationship Between Ocular Itch, Ocular Pain, and Dry Eye Symptoms (An American Ophthalmological Society Thesis)

PubMed Central

Galor, Anat; Small, Leslie; Feuer, William; Levitt, Roy C.; Sarantopoulos, Konstantinos D.; Yosipovitch, Gil

2017-01-01

Purpose To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs. Methods A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch. Results The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate-severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate-severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms. Conclusions Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity. PMID:29391860

Goblet cell response after photorefractive keratectomy and laser in situ keratomileusis

PubMed Central

Ryan, Denise S.; Bower, Kraig S.; Sia, Rose K.; Shatos, Marie A.; Howard, Robin S.; Mines, Michael J.; Stutzman, Richard D.; Dartt, Darlene A.

2017-01-01

PURPOSE To determine whether patients without dry eye preoperatively have an altered conjunctival goblet cell density and mucin secretion postoperatively and to explore what factors affect changes in goblet cell density and mucin secretion. SETTING The former Walter Reed Army Medical Center, Washington, DC, USA. DESIGN Prospective nonrandomized clinical study. METHODS Impression cytology was used to determine conjunctival goblet cell density before and 1 week, 1 month, and 3 months after photorefractive keratectomy (PRK) or laser in situ keratomileusis (LASIK). The McMonnies questionnaire, Schirmer test, tear breakup time, corneal sensitivity, rose bengal staining, and computerized videokeratoscopy were also performed to assess tear-film and ocular-surface health. RESULTS The ratio of goblet cell to total cells changed postoperatively from baseline in both groups (P < .001). The most significant change was a median 29% decrease 1 month postoperatively. However, there were no significant differences between groups over time (P = .772). The ratio of filled goblet cell to total goblet cell did not change significantly over the same time period (P = .128), and there were no significant differences between the PRK group and the LASIK group over time (P = .282). CONCLUSIONS Patients without apparent dry eye had altered conjunctival goblet cell population after PRK or LASIK. The conjunctival goblet cell population tended to decrease in the early postoperative period after either surgery and was most affected by preoperative goblet cell density. The changes in the tear film and ocular surface did not seem to affect goblet cell mucin secretion after either procedure. PMID:27531295

Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium

PubMed Central

Ouyang, Hong; Goldberg, Jeffrey L.; Chen, Shuyi; Li, Wei; Xu, Guo-Tong; Li, Wei; Zhang, Kang; Nussenblatt, Robert B.; Liu, Yizhi; Xie, Ting; Chan, Chi-Chao; Zack, Donald J.

2016-01-01

Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases. PMID:27102165

A Comparison of the Effects of Benzalkonium Chloride on Ocular Surfaces between C57BL/6 and BALB/c Mice

PubMed Central

Yang, Qian; Zhang, Yafang; Liu, Xiuping; Wang, Nan; Song, Zhenyu; Wu, Kaili

2017-01-01

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with BAC eye-drops at different concentrations. Eyes were evaluated by scoring epithelial disruption, corneal opacity and neovascularization in vivo, and by histological assays with hematoxylin/eosin (H/E) and periodic acid-Schiff stainings and by determining the expression of inflammatory factors in vitro on Days 7 and 14. The in vivo corneal epithelial disruption, corneal edema/opacity and neovascularization, which were in accordance with the results of the H/E staining and peaked at Day 7, were observed in a dose-dependent manner in the BAC-treated mice, with more severe signs in the C57BL/6 mice than the BALB/c mice. The loss of conjunctival goblet cells in the conjunctivas and the increasing expression of monocyte chemoattractant protein 1 (MCP-1), growth-regulated protein alpha (GROa) and macrophage inflammatory protein-1 alpha (MIP-1a) in the corneas were found in a dose-dependent manner in both strains of mice. Topical application of BAC can dramatically disrupt the ocular surfaces of C57BL/6 and BALB/c mice, and the disruptions were much more severe in the C57BL/6 mice that received high doses of BAC. PMID:28245636

P63 EXPRESSION LEVELS IN SIDE POPULATION AND LOW LIGHT SCATTERING OCULAR SURFACE EPITHELIAL CELLS

PubMed Central

Epstein, Seth P; Wolosin, J. Mario; Asbell, Penny A

2005-01-01

Purpose Because stem cells exhibit high self-renewal capacity, slow cycling, and high proliferative potential, and one of many markers postulated for epithelial stem cells, p63, is challenged by widespread expression within stem cell–free regions, we examined p63 expression in these stem cell–associated cohorts compared with their controls. Methods Rabbit limbocorneal cryosections, cytospun cell-sorted (by fluorescence-activated cell sorter) side population (SP) and low side scatter (LSSC) cells, and limbal epithelial cells over feeders were stained for p63 by indirect immunofluorescence. Clones were fixed and stained daily for 7 days. Image analysis measured p63 intensity, plotting it against colony size. Results All basal limbal cells were positive for p63, yet only 5% to 7% expressed high p63 intensities, 40% intermediate, and the majority low. Side population cells were less than 1% of total cells. The average intensity of SP staining was three times that of controls. Subpopulations displaying stemlike features exhibited highest p63 expression. Replication rates of isolated cells differed. Day 5 colonies contained 256 (16 hours/cycle) to two (96 hours/cycle) cells. Whereas all cells were positive for p63, intensity in slow-cycling cells was three to four times that in rapidly proliferating congeners. Increased cell doublings did not decrease fluorescence. Conclusions Results suggest that p63 concentration is maximal in stem cells and decreases with differentiation. High p63 levels seem to correlate with cells of the SP and LSSC phenotypes, indicating high cell stemness. With identification of stem cells, further studies can elucidate their use in supporting ocular surface health. PMID:17057802

Two Patients with Dry Eye Disease Followed Up Using an Expression Assay of Ocular Surface Mucin.

PubMed

Machida, Yumiko; Shoji, Jun; Harada, Natsuko; Inada, Noriko

2016-01-01

We report 2 patients with dry eye disease followed up using the expression levels of ocular surface mucin. Patient 1: a 57-year-old woman with Sjögren's syndrome-associated dry eyes experienced severe dryness and foreign body sensation in both her eyes, and instilled sodium hyaluronate ophthalmic solution 0.3% about 10-15 times daily. We measured the expression levels of MUC5AC mRNA (MUC5AC) and MUC16 mRNA (MUC16) by using real-time reversed transcription polymerase chain reaction for the specimens of modified impression cytology. Expression levels of MUC5AC and MUC16 on her ocular surface were very low. Subjective symptoms and expression levels of ocular surface mucin improved after combined treatment of rebamipide (4 times daily) and fluorometholone (once daily) ophthalmic suspension. Patient 2: a 62-year-old man with chronic graft-versus-host disease-associated dry eye experienced severe foreign body sensation and developed superficial punctate keratopathy with mucous thread and filamentary keratitis. Expression level of MUC5AC was very high at baseline. Subjective symptoms and expression levels of ocular surface mucin improved by combined treatment of rebamipide (4 times daily) and fluorometholone (once daily) ophthalmic suspension. Clinical test for MUC gene expression on the ocular surface was found to be useful in the follow-up of dry eye treatment.

Cornea and ocular lens visualized with three-dimensional confocal microscopy

NASA Astrophysics Data System (ADS)

Masters, Barry R.

1992-08-01

This paper demonstrates the advantages of three-dimensional reconstruction of the cornea and the ocular crystalline lens by confocal microscopy and volume rendering computer techniques. The advantages of noninvasive observation of ocular structures in living, unstained, unfixed tissue include the following: the tissue is in a natural living state without the artifacts of fixation, mechanical sectioning, and staining; the three-dimensional structure can be observed from any view point and quantitatively analyzed; the dynamics of morphological changes can be studied; and the use of confocal microscopic observation results in a reduction of the number of animals required for ocular morphometric studies. The main advantage is that the dynamic morphology of ocular structures can be investigated in living ocular tissue. A laser scanning confocal microscope was used in the reflected light mode to obtain the two- dimensional images from the cornea and the ocular lens of a freshly enucleated rabbit eye. The light source was an argon ion laser with 488 nm wavelength. The microscope objective was a Leitz 25X, NA 0.6 water immersion lens. The 400 micron thick cornea was optically sectioned into 133, three micron sections. The semi-transparent cornea and the in-situ ocular lens was visualized as high resolution, high contrast two-dimensional images. The under sampling resulted in a three-dimensional visualization rendering in which the corneal thickness (z-axis) is compressed. The structures observed in the cornea include: superficial epithelial cells and their nuclei, basal epithelial cells and their `beaded' cell borders, basal lamina, nerve plexus, nerve fibers, free nerve endings in the basal epithelial cells, nuclei of stromal keratocytes, and endothelial cells. The structures observed in the in-situ ocular lens include: lens capsule, lens epithelial cells, and individual lens fibers.

Use of Adipose-Derived Mesenchymal Stem Cells in Keratoconjunctivitis Sicca in a Canine Model

PubMed Central

Villatoro, Antonio J.; Fernández, Viviana; Rico-Llanos, Gustavo A.; Becerra, José; Andrades, José A.

2015-01-01

Keratoconjunctivitis sicca (KCS) or dry eye disease (DED) is an immune-mediated multifactorial disease, with high level of prevalence in humans and dogs. Our aim in this study was to investigate the therapeutic effects of allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) implanted around the lacrimal glands in 12 dogs (24 eyes) with KCS, which is refractory to current available treatments. Schirmer tear test (STT) and ocular surface integrity were assessed at 0 (before treatment), 3, 6, and 9 months after treatment. Average STT values and all clinical signs showed a statistically significant change (P < 0.001) during the follow-up with reduction in all ocular parameters scored: ocular discharge, conjunctival hyperaemia, and corneal changes, and there were no signs of regression or worsening. Implanted cells were well tolerated and were effective reducing clinical signs of KCS with a sustained effect during the study period. None of the animals showed systemic or local complications during the study. To our knowledge, this is the first time in literature that implantation of allogeneic Ad-MSCs around lacrimal glands has been found as an effective therapeutic alternative to treat dogs with KCS. These results could reinforce a good effective solution to be extrapolated to future studies in human. PMID:25802852

Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease.

PubMed

Paton, D M

2016-09-01

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

Effect of Autologous Serum Eye Drops in Patients with Sjögren Syndrome-related Dry Eye: Clinical and In Vivo Confocal Microscopy Evaluation of the Ocular Surface.

PubMed

Semeraro, Francesco; Forbice, Eliana; Nascimbeni, Giuseppe; Taglietti, Marco; Romano, Vito; Guerra, Germano; Costagliola, Ciro

To evaluate in vivo changes after therapy using autologous serum (AS) eye drops in Sjögren's syndrome (SS)-related dry eyes by confocal microscopy. In this study, 24 patients with SS-related dry eyes [12 in AS eye drop therapy and 12 in artificial tear (AT) therapy] and 24 healthy volunteers were recruited. Ocular Surface Disease Index (OSDI), central corneal thickness, tear film, break-up time, corneal and conjunctival staining, Schirmer's test and corneal confocal microscopy were investigated. Tear production, tear stability, corneal staining, inflammation, and central corneal thickness, Langherans cells, activated keratocytes, intermediate epithelial cell density, nerve tortuosity, number of sub-basal nerve branches, and number of bead-like formations differed between patients and controls (p<0.0001). The AT and AS groups differed in the OSDI, number of branches, and number of beadings (p<0.0001). AS eye drops improve symptoms and confocal microscopy findings in SS-related dry eyes. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

In vitro methods of assessing ocular biocompatibility using THP-1-derived macrophages.

PubMed

McCanna, David Joseph; Barthod-Malat, Aurore V; Gorbet, Maud B

2015-01-01

Macrophages play an important role in the elimination of infections, the removal of debris and in tissue repair after infection and trauma. In vitro models that assess ocular biomaterials for toxicity typically focus on the effects of these materials on epithelial or fibroblast cells. This investigation evaluated known ocular toxins deposited on model materials for their effects on the viability and activation of macrophages. THP-1-derived macrophages were cultured onto silicone films (used as a base biomaterial) deposited with chemical toxins (benzalkonium chloride (BAK), zinc diethyldithiocarbamate (ZDEC) and lipopolysaccharide (LPS)). Utilizing three fluorescent dyes calcein, ethidium homodimer-1 (EthD-1) and annexin V, the viability of macrophages attached to the biomaterial was determined using confocal microscopy. Propidium iodide (PI) staining and alamarBlue® (resazurin) reduction were used to assess cell death and metabolic activity. CD14, CD16, CD33, CD45, and CD54 expression of adherent macrophages, were also evaluated to detect LPS activation of macrophages using flow cytometry. The sensitivity of this test battery was demonstrated as significant toxicity from treated surfaces with ZDEC (0.001-0.01%), and BAK (0.001%-0.1%) was detected. Also, macrophage activation could be detected by measuring CD54 expression after exposure to adsorbed LPS. These in vitro methods will be helpful in determining the toxicity potential of new ocular biomaterials.

The Effect of Ambient Titanium Dioxide Microparticle Exposure to the Ocular Surface on the Expression of Inflammatory Cytokines in the Eye and Cervical Lymph Nodes.

PubMed

Eom, Youngsub; Song, Jong Suk; Lee, Hyun Kyu; Kang, Boram; Kim, Hyeon Chang; Lee, Hyung Keun; Kim, Hyo Myung

2016-12-01

To investigate the ocular immune response following exposure to airborne titanium dioxide (TiO2) microparticles. Rats in the TiO2-exposed group (n = 10) were exposed to TiO2 particles for 2 hours twice daily for 5 days, while the controls (n = 10) were not. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage, serum immunoglobulin (Ig) G and E were assayed by using enzyme-linked immunosorbent assay, and the size of cervical lymph nodes was measured. In addition, the expression of interleukin (IL)-4, IL-17, and interferon (IFN)-γ in the anterior segment of the eyeball and cervical lymph nodes was measured by immunohistochemistry, real-time reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analysis. Median corneal staining score (3.0), tear LDH activity (0.24 optical density [OD]), and cervical lymph node size (36.9 mm2) were significantly higher in the TiO2-exposed group than in the control group (1.0, 0.13 OD, and 26.7 mm2, respectively). Serum IgG and IgE levels were found to be significantly elevated in the TiO2-exposed group (P = 0.021 and P = 0.021, respectively). Interleukin 4 expression was increased in the anterior segment of the eyeball and lymph nodes following TiO2 exposure, as measured by immunostaining, real-time RT-PCR, and Western blot. In addition, IL-17 and IFN-γ levels were also increased following TiO2 exposure compared to controls as measured by immunostaining. Exposure to airborne TiO2 induced ocular surface damage. The Type 2 helper T-cell pathway seems to play a dominant role in the ocular immune response following airborne TiO2 exposure.

Amniotic membrane traps and induces apoptosis of inflammatory cells in ocular surface chemical burn

PubMed Central

Liu, Ting; Zhai, Hualei; Xu, Yuanyuan; Dong, Yanling; Sun, Yajie; Zang, Xinjie

2012-01-01

Purpose Severe chemical burns can cause necrosis of ocular surface tissues following the infiltration of inflammatory cells. It has been shown that amniotic membrane transplantation (AMT) is an effective treatment for severe chemical burns, but the phenotypes of cells that infiltrate the amniotic membrane and the clinical significance of these cellular infiltrations have not previously been reported. The present work studies the inflammation cell traps and apoptosis inducing roles of the amniotic membrane after AMT in patients with acute chemical burns. Methods A total of 30 patients with acute alkaline burns were classified as having either moderate or severe burns. In all participants, AMT was performed within one week of his/her injury. After 7–9 days, the transplanted amniotic membranes were removed. Histopathological and immunohistochemical techniques were used for the examination and detection of infiltrating cells, and tests for the expression of CD (cluster of differentiation)15, CD68, CD3, CD20, CD57, CD31, CD147, and CD95 (Fas) were performed. A TUNEL (TdT-mediated dUTP nick end labeling) assay was used to confirm apoptosis of the infiltrating cells. Three patients with herpes simplex-induced keratitis who had undergone AMT to treat persistent epithelium defects were used as a control group. Amniotic membrane before transplantation was used as another control. Results After amniotic membrane transplantation, the number of infiltrating cells in patients with severe burns was significantly higher than in patients with moderate burns or in control patients (p<0.05). Among the severe burns patients, CD15 and CD68 were widely expressed in the infiltrating cells, and CD3, CD20, and CD57 were only found in a small number of cells. Occasionally, CD31-positive cells were found in the amniotic membranes. More cells that were CD147, Fas, and TUNEL positive were found in patients with severe burns than in patients with moderate burns or in control patients. Conclusions Neutrophils and macrophages were the main cells that had infiltrated into the amniotic membrane during the acute phase of healing from a chemical burns. AMT can trap different inflammatory cells and induce apoptosis of inflammatory cells in acute ocular chemical burns. PMID:22876141

The effects of 3% diquafosol sodium application on the tear functions and ocular surface of the Cu,Zn-superoxide dismutase-1 (Sod1)-knockout mice.

PubMed

Kojima, Takashi; Dogru, Murat; Ibrahim, Osama M; Nagata, Taeko; Higa, Kazunari; Shimizu, Takahiko; Shirasawa, Takuji; Satake, Yoshiyuki; Shimazaki, Seika; Shimazaki, Jun; Tsubota, Kazuo

2014-01-01

To investigate the role of a water and mucin secretagogue (3% diquafosol sodium eye drops) on the tear function and conjunctival ocular surface changes in Sod1(-/-) in comparison to the wild-type (WT) mice. Fourteen eyes of 7 Sod1(-/-) male mice with C57BL/background and 14 eyes of 7 C57BL6 strain wild-type male mice were examined at 40 weeks in this study. All mice had application of 3% diquafosol ophthalmic solution six times a day for 2 weeks. Tear film stability and corneal epithelial damage was evaluated by fluorescein and Rose Bengal stainings. Anterior segment photography was performed before and after eye drop instillations. Aqueous tear quantity was measured with phenol red-impregnated cotton threads without anesthesia. Animals were sacrificed at 42 weeks after diquafosol treatment and the whole globe specimens were subjected to periodic acid Schiff staining. Goblet cell density was quantified by J Image software. Quantitative real-time PCR for conjunctival muc 5AC messenger RNA expression was also performed. Sod1(-/-) mice had significantly higher fluorescein staining scores compared to the WT mice before eye drop instillation. The mean tear film breakup time, Rose Bengal staining scores, and muc5 messenger RNA expression improved significantly with diquafosol treatment in both the WT and the knockout mice. The mean fluorescein staining score and aqueous tear quantity significantly improved in the Sod1(-/-) mice with treatment. A notable and consistent increase in goblet cells and decrease in inflammatory cell infiltrates could be confirmed in all specimens after 2 weeks of diquafosol eye drop application. Three percent diquafosol ophthalmic solution appears to be effective in the treatment of ocular surface disease in this age-related dry eye disease mouse model.

MUC19 expression in human ocular surface and lacrimal gland and its alteration in Sjögren syndrome patients.

PubMed

Yu, D F; Chen, Y; Han, J M; Zhang, H; Chen, X P; Zou, W J; Liang, L Y; Xu, C C; Liu, Z G

2008-02-01

This study investigated the expression of MUC19, a newly discovered gel-forming mucin gene, in normal human lacrimal functional unit components and its alteration in Sjögren syndrome patients. Real-time PCR and immunohistochemistry were performed to determine the expression of MUC19 and MUC5AC in human cornea, conjunctiva, and lacrimal gland tissues. Conjunctival impression cytology specimens were collected from normal control subjects and Sjögren syndrome patients for Real-time PCR, PAS staining, and immunohistochemistry assays. In addition, conjunctiva biopsy specimens from both groups were examined for the expression differences of MUC19 and MUC5AC at both mRNA and protein level. The MUC19 mRNA was found to be present in cornea, conjunctiva and lacrimal gland tissues. The immunohistochemical staining of mucins showed that MUC19 was expressed in epithelial cells from corneal, conjunctival, and lacrimal gland tissues. In contrast, MUC5AC mRNA was only present in conjunctiva and lacrimal gland tissues, but not in cornea. Immunostaining demonstrates the co-staining of MUC19 and MUC5AC in conjunctival goblet cells. Consistent with the significant decrease of mucous secretion, both MUC19 and MUC5AC were decreased in conjunctiva of Sjögren syndrome patients compared to normal subjects. Considering the contribution of gel-forming mucins to the homeostasis of the ocular surface, the decreased expression of MUC19 and MUC5AC in Sjögren syndrome patients suggested that these mucins may be involved in the disruption of the ocular surface homeostasis in this disease.

How Ocular Surface Disease Impacts the Glaucoma Treatment Outcome

PubMed Central

Kaštelan, Snježana; Tomić, Martina; Metež Soldo, Kata; Salopek-Rabatić, Jasminka

2013-01-01

The treatment goals for glaucoma are lowering the intraocular pressure and preservation of vision. Topical hypotensive drops are the standard form of therapy which is often associated with some symptoms of toxicity, ocular inflammation, allergy, or ocular surface disease (OSD). OSD is a common comorbidity in glaucoma patients, and its prevalence with glaucoma increases with age. Use of topical treatment could additionally increase symptoms of OSD mostly due to preservatives added to multidose medication bottles used to reduce the risk of microbial contamination. This toxicity has been particularly associated with BAK, the most commonly used preservative which damages conjunctival and corneal epithelial cells and significantly aggravates OSD symptoms. OSD adversely affects patients' quality of life causing discomfort and problems with vision which in turn may result in noncompliance, lack of adherence, and eventually visual impairment. In the management of glaucoma patients OSD symptoms should not be overlooked. If they are present, topical glaucoma treatment should be adapted by decreasing the amount of drops instilled daily, using BAK-free or preservative-free medication and lubricants if necessary. Awareness of the presence and importance of OSD will in turn improve patients' adherence and compliance and thus ultimately the preservation of long-term vision. PMID:24224176

Development of a second-generation novel UVR sensor for the quantification of the light field at the anterior ocular surface

NASA Astrophysics Data System (ADS)

Fleming, David; Walsh, James E.; Moore, Linda; Bergmanson, Jan P. G.; McMahon, David

2005-06-01

Research has shown in recent years that acute and cumulative exposure to excessive ultraviolet radiation (UVR) can cause a range of degenerative ocular conditions such as pterygium, photokeratitis and pinguecula. The increase in natural solar UVR as a result of the depletion of the ozone layer has led to a greater awareness of the adverse effects of UVR on the anterior ocular surface tissues. The relevance of this lies in the fact that these tissues are not immune to photodamage and that there is selective absorption of UVR by conjunctival and corneal tissue in the anterior ocular surface. Therefore, there is a demand for more precise quantification and localisation of UVR incidence at the anterior ocular surface. A novel solar blind photodiode sensor array has been designed, constructed and tested for this purpose. The emphasis of the measurements made by this sensor system is the acquisition of real time, field based surveys of the ocular UVR light field in a broad range of insolation environments. These data will then provide a thorough database of UVR irradiances that can be related to induced damage of anterior ocular tissue. Results to date show the first measured, in-vivo, absolute UVR levels on the eye, the corresponding relative field across the eye and the presence of nasal-temporal biases that exist.

Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits

PubMed Central

Liang, H.; Brignole-Baudouin, F.; Rabinovich-Guilatt, L.; Mao, Z.; Riancho, L.; Faure, M.O.; Warnet, J.M.; Lambert, G.

2008-01-01

Purpose To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK), and cetalkonium chloride (CKC), in standard solution or cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches. Methods Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 µl of phosphate-buffered saline (PBS), PBS containing 0.02% BAK or 0.002% CKC (BAK Sol and CKC Sol, respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface changes induced by these eye drops were investigated using slit-lamp examination, flow cytometry (FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)+ apoptotic cells. Results Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4 h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes. Conclusions The acute administration of 15 instillations at 5 min intervals was a rapid and efficient model to assess quaternary ammonium toxicity profiles. This model showed the highest toxicity, induced by the BAK solution, and the lowest level of toxicity, induced by the CKC emulsion. These in vivo and ex vivo experimental approaches demonstrated that ocular surface toxicity was reduced by using an emulsion instead of a traditional solution and that a CKC emulsion was safe for future ocular administration. PMID:18347566

Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits.

PubMed

Liang, H; Brignole-Baudouin, F; Rabinovich-Guilatt, L; Mao, Z; Riancho, L; Faure, M O; Warnet, J M; Lambert, G; Baudouin, C

2008-01-31

To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK), and cetalkonium chloride (CKC), in standard solution or cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches. Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 microl of phosphate-buffered saline (PBS), PBS containing 0.02% BAK or 0.002% CKC (BAK Sol and CKC Sol, respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface changes induced by these eye drops were investigated using slit-lamp examination, flow cytometry (FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)+ apoptotic cells. Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4 h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes. The acute administration of 15 instillations at 5 min intervals was a rapid and efficient model to assess quaternary ammonium toxicity profiles. This model showed the highest toxicity, induced by the BAK solution, and the lowest level of toxicity, induced by the CKC emulsion. These in vivo and ex vivo experimental approaches demonstrated that ocular surface toxicity was reduced by using an emulsion instead of a traditional solution and that a CKC emulsion was safe for future ocular administration.

In Vivo Confocal Microscopic Evaluation of Corneal Langerhans Cells in Dry Eye Patients§

PubMed Central

Machetta, Federica; Fea, Antonio M; Actis, Alessandro G; de Sanctis, Ugo; Dalmasso, Paola; Grignolo, Federico M

2014-01-01

Purpose. To assess inflammatory involvement of cornea in dry eye by means of confocal microscopy, evaluating the presence and distribution of Langherans cells (LCs). Methods: 98 eyes of 49 subjects were enrolled: 18 subjects affected by Sjögren Syndrome Dry Eye (SSDE), 17 with Non-Sjögren Syndrome Dry Eye (NSSDE), 14 healthy volunteeers. Dry eye symptoms, tear film, ocular surface damage and corneal confocal microscopy were analized. Results: A significant increase of LCs density was observed at sub-basal nerve plexus (SSDE = 79 cells/mm2 andNDE = 22 cells/mm2; p = 0,0031) and sub-epithelial nerve plexus (SSDE = 38 cells/mm2 and NDE = 3 cells/mm2; p = 0,0169) in central cornea of SSDE group. An increased number of LCs from the center to the periphery of the cornea was observed, significant only in healthy volunteers group. In dry eye patients there was an increase in LCs density in both peripheral and central cornea with a significant difference between NDE (14,66 cells/mm2) and SSDE (56,66 cells/mm2) only in central cornea (p = 0,0028). In SSDE group, mean density of LCs in central cornea results also superior to NSSDE group (29,33 cells/mm2). There was no correlation between LCs density and dry eye symptoms, tear film deficiency and ocular surface damage. Conclusion: This study demonstrates the activation of an inflammatory and immunological reaction in cornea of NSSDE and SSDE patients. Confocal microscopy can be an important diagnostic tool in evaluation and follow-up of dry eye disease. PMID:25317216

Clinical Features and Treatment of Ocular Toxoplasmosis

PubMed Central

Park, Young-Hoon

2013-01-01

Ocular toxoplasmosis is a disease caused by the infection with Toxoplasma gondii through congenital or acquired routes. Once the parasite reaches the retina, it proliferates within host cells followed by rupture of the host cells and invasion into neighboring cells to make primary lesions. Sometimes the restricted parasite by the host immunity in the first scar is activated to infect another lesion nearby the scar. Blurred vision is the main complaint of ocular toxoplasmic patients and can be diagnosed by detection of antibodies or parasite DNA. Ocular toxoplasmosis needs therapy with several combinations of drugs to eliminate the parasite and accompanying inflammation; if not treated it sometimes leads to loss of vision. We describe here clinical features and currently available chemotherapy of ocular toxoplasmosis. PMID:24039281

Clinical features and treatment of ocular toxoplasmosis.

PubMed

Park, Young-Hoon; Nam, Ho-Woo

2013-08-01

Ocular toxoplasmosis is a disease caused by the infection with Toxoplasma gondii through congenital or acquired routes. Once the parasite reaches the retina, it proliferates within host cells followed by rupture of the host cells and invasion into neighboring cells to make primary lesions. Sometimes the restricted parasite by the host immunity in the first scar is activated to infect another lesion nearby the scar. Blurred vision is the main complaint of ocular toxoplasmic patients and can be diagnosed by detection of antibodies or parasite DNA. Ocular toxoplasmosis needs therapy with several combinations of drugs to eliminate the parasite and accompanying inflammation; if not treated it sometimes leads to loss of vision. We describe here clinical features and currently available chemotherapy of ocular toxoplasmosis.

Tear film and ocular surface assessment in psoriasis.

PubMed

Aragona, Emanuela; Rania, Laura; Postorino, Elisa Imelde; Interdonato, Alberto; Giuffrida, Roberta; Cannavò, Serafinella Patrizia; Puzzolo, Domenico; Aragona, Pasquale

2018-03-01

Psoriasis is a skin disease with also systemic involvement: its impact on the eye is not well established and often clinically underestimated. Aim of this study was to investigate the presence of ocular discomfort symptoms and of ocular surface changes in a population of patients with psoriasis. For this cross-sectional, comparative study, 66 patients with psoriasis were subdivided according to the presence of arthritis and to the use of biological therapy. All patients underwent clinical evaluation with the following tests: Ocular Surface Disease Index Questionnaire, Tearscope examination, meibometry, tear film breakup time, corneal and conjunctival fluorescein staining, Schirmer I test, corneal aesthesiometry, meibomian gland dysfunction (MGD) assessment and conjunctival impression cytology. 28 healthy subjects were also enrolled and treated with the same clinical tests. A statistical analysis of the results was performed. Patients with psoriasis showed a significant deterioration of the ocular surface tests, if compared with healthy subjects, demonstrated by tear film lipid layer alteration, tear film instability, corneal and conjunctival epithelial suffering and mild squamous metaplasia at impression cytology. No differences were found in ocular surface test results of the psoriatic group when patients were divided according to the presence of arthritis, whereas the anti-inflammatory treatment with biological drugs demonstrated a significant improvement of corneal stain and MGD. Our findings suggest that the ocular surface involvement in patients with psoriasis indicates the need of periodic ophthalmological examinations to diagnose the condition and allow a proper treatment, so contributing to the amelioration of patients' quality of life. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

An increase in circulating B cell-activating factor in childhood-onset ocular myasthenia gravis.

PubMed

Motobayashi, Mitsuo; Inaba, Yuji; Nishimura, Takafumi; Kobayashi, Norimoto; Nakazawa, Yozo; Koike, Kenichi

2015-04-01

Myasthenia gravis is a B cell-mediated autoimmune disorder. The pathophysiology of childhood-onset ocular myasthenia gravis remains unclear. We investigated serum B cell-activating factor levels and other immunological parameters in child patients with ocular myasthenia gravis. Blood samples were obtained from 9 children with ocular myasthenia gravis and 20 age-matched controls. We assayed serum concentrations of B cell-activating factor, anti-acetylcholine receptor antibody titers, 7 types of cytokines (interleukins-2, -4, -6, -10, and -17A; interferon-γ; tumor necrosis factor-α) as well as the percentages of peripheral blood CD4+, CD8+, and CD19+ cells. Serum B cell-activating factor levels were significantly higher before immunosuppressive therapy in patients with childhood-onset ocular myasthenia gravis than in controls and decreased after immunosuppressive therapy. A significant positive correlation was observed between serum B cell-activating factor levels and anti-acetylcholine receptor antibody titers in patients with myasthenia gravis. Serum B cell-activating factor concentrations did not correlate with the percentages of CD4+, CD8+, and CD19+ cells or the CD4+/CD8+ ratio. No significant differences were observed in the levels of the 7 different types of cytokines examined, including interleukin-17A, between preimmunosuppressive therapy myasthenia gravis patients and controls. Circulating B cell-activating factor may play a key role in the pathophysiology of childhood-onset ocular myasthenia gravis. Copyright © 2015 Elsevier Inc. All rights reserved.

Modeling of mouse eye and errors in ocular parameters affecting refractive state

NASA Astrophysics Data System (ADS)

Bawa, Gurinder

Rodents eye are particularly used to study refractive error state of an eye and development of refractive eye. Genetic organization of rodents is similar to that of humans, which makes them interesting candidates to be researched upon. From rodents family mice models are encouraged over rats because of availability of genetically engineered models. Despite of extensive work that has been performed on mice and rat models, still no one is able to quantify an optical model, due to variability in the reported ocular parameters. In this Dissertation, we have extracted ocular parameters and generated schematics of eye from the raw data from School of Medicine, Detroit. In order to see how the rays would travel through an eye and the defects associated with an eye; ray tracing has been performed using ocular parameters. Finally we have systematically evaluated the contribution of various ocular parameters, such as radii of curvature of ocular surfaces, thicknesses of ocular components, and refractive indices of ocular refractive media, using variational analysis and a computational model of the rodent eye. Variational analysis revealed that variation in all the ocular parameters does affect the refractive status of the eye, but depending upon the magnitude of the impact those parameters are listed as critical or non critical. Variation in the depth of the vitreous chamber, thickness of the lens, radius of the anterior surface of the cornea, radius of the anterior surface of the lens, as well as refractive indices for the lens and vitreous, appears to have the largest impact on the refractive error and thus are categorized as critical ocular parameters. The radii of the posterior surfaces of the cornea and lens have much smaller contributions to the refractive state, while the radii of the anterior and posterior surfaces of the retina have no effect on the refractive error. These data provide the framework for further refinement of the optical models of the rat and mouse eye and suggest that extra efforts should be directed towards increasing the linear resolution of the rodent eye biometry and obtaining more accurate data for the refractive indices of the lens and vitreous.

Scleral Lenses in the Management of Corneal Irregularity and Ocular Surface Disease.

PubMed

Shorter, Ellen; Harthan, Jennifer; Nau, Cherie B; Nau, Amy; Barr, Joseph T; Hodge, David O; Schornack, Muriel M

2017-09-29

To describe current practice patterns regarding the use of scleral lens therapy in the management of corneal irregularity and ocular surface disease among eye care providers who fit scleral lenses. The Scleral Lenses in Current Ophthalmic Practice: an Evaluation (SCOPE) study group conducted an electronic survey of eye care providers from January 15 to March 31, 2015. Respondents ranked management options for corneal irregularity in the order in which they would generally consider their use. Respondents also ranked options for the management of ocular surface disease in the order in which they would use each of the treatments. Results for each option were analyzed as percentage first-place ranking; percentage first-, second-, or third-place ranking; and mean rank score. Survey responses were obtained from 723 providers who had fit 5 or more scleral lenses. Of these respondents, 629 ranked options for management of corneal irregularity and 612 ranked options for management of ocular surface disease. Corneal rigid gas-permeable lenses were the first option for management of corneal irregularity for 44% of respondents, and scleral lenses were the first option for 34% of respondents. Lubricant drops were the first therapeutic recommendation for ocular surface disease for 84% of respondents, and scleral lenses were ranked first by 6% of respondents. Scleral lenses rank second only to corneal rigid gas-permeable lenses for management of corneal irregularity. Scleral lenses are generally considered after other medical intervention and before surgery for the management of ocular surface disease.

[Ocular Surface Evaluation in Patients Treated with Prostaglandin Analogues Considering Preservative Agent].

PubMed

Mlčáková, E; Mlčák, P; Karhanová, M; Langová, K; Marešová, K

The aim of this study was to evaluate the ocular surface in patients treated with prostaglandin analogues considering contained preservative agent. 60 patients with glaucoma or ocular hypertension treated with prostaglandin analogue monotherapy were enrolled in this observational study. 20 patients with glaucoma suspect or ocular hypertension without local or systemic glaucoma medication formed the control group. Demographic data and medical history were recorded for each participant. Patients filled in the Ocular surface disease index© (OSDI) questionnaire and underwent an ophthalmological examination including assessment of conjunctival hyperaemia according to Efron, tear film break up time (BUT) and fluorescein staining according to the Oxford grading scheme. Treated participants were divided into 3 groups according to the preservative contained in the currently used prostaglandin analogue: the preservative-free group (18 patients), the polyquaternium group (17 patients) and the benzalkonium chloride (BAK) group (25 patients). The control group had significantly lower fluorescein staining than the preservative-free group (p=0.001), the polyquaternium group (p=0.007) and the BAK group (p=0.002). The conjunctival hyperaemia was significantly lower in the preservative-free group compared to the polyquaternium group (p=0.011). There was no significant difference among the other groups. The difference neither in the OSDI score nor in the BUT was statistically important. This study confirmed that the ocular surface is worse in patients treated with prostaglandin analogue monotherapy than in people without glaucoma medication. A significant difference among treated patients depending on a preservative agent was not proved.Key words: benzalkonium chloride, glaucoma, ocular surface disease, preservatives, prostaglandin analogues.

The effects of 2 week senofilcon-A silicone hydrogel contact lens daily wear on tear functions and ocular surface health status.

PubMed

Dogru, Murat; Ward, Samantha K; Wakamatsu, Tais; Ibrahim, Osama; Schnider, Cristina; Kojima, Takashi; Matsumoto, Yukihiro; Ogawa, Junko; Shimazaki, Jun; Tsubota, Kazuo

2011-04-01

To prospectively investigate the effects of 2 week senofilcon A contact lens (CL) daily wear on the functional visual acuity (VA), ocular surface and tear film. Seventeen right eyes of 17 senofilcon A CL wearers without any ocular or systemic diseases were examined before and 2 weeks after lens wear. Visual acuity measurements, tear evaporation rate, ELISA for tear cytokines, strip meniscometry, tear lipid layer interferometry, tear film break-up time (BUT), in vivo confocal microscopy, corneal sensitivity, ocular surface vital staining, Schirmer I test and brush cytology for MUC5AC mRNA expression were performed before and after CL wear. The best corrected Landolt VA, functional VA parameters, the mean lipid layer interferometry grades, tear evaporation rates, Schirmer test values, vital staining scores and in vivo confocal microscopy parameters did not show any significant differences after 2 weeks of CL wear. The tear film BUT showed a significant decrease together with a significant down regulation of MUC5 AC mRNA expression after CL wear. A statistically significant elevation in the mean tear interleukin (IL)-6 concentration was also observed after 2 weeks of CL wear. Two week senofilcon A daily CL wear seems to be associated with tear instability, a decrease in MUC5AC expression, and elevation of IL-6 in tears without significant alterations in epithelial damage scores or in the morphology or density of in vivo keratoconjunctival cells and nerves. Alterations associated with long term wear and patients with dry eye disease need to be studied in future trials. Copyright © 2010 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Therapeutic potential of trichostatin A to control inflammatory and fibrogenic disorders of the ocular surface.

PubMed

Kitano, Ai; Okada, Yuka; Yamanka, Osamu; Shirai, Kumi; Mohan, Rajiv R; Saika, Shizuya

2010-12-31

To examine the effects of a histone deacetylase inhibitor, Trichostatin A (TSA), on the behavior of macrophages and subconjunctival fibroblasts in vitro and on ocular surface inflammation and scarring in vivo using an alkali burn wound healing model. Effects of TSA on expression of inflammation-related growth factors or collagen I were examined by real-time RT-PCR or immunoassay in mouse macrophages or human subconjunctival fibroblasts. Effects of TSA on trans forming growth factor β (TGFβ)/Smad signaling were evaluated with western blotting and/or immunocytochemistry. Alkali-burn injuries on the eyes of mice were performed with three µl of 0.5 N NaOH under general and topical anesthesia. TSA (600 µg/Kg daily) or vehicle was administered to animals via intraperitoneal (i.p.) injection. Histology and real-time RT-PCR investigations evaluated the effects of TSA on the healing process of the cornea. TSA inhibited TGFβ 1 and vascular endothelial growth factor (VEGF) expression in macrophages, and TGFβ1 and collagen I in ocular fibroblasts. It elevated the expression of 5'-TG-3'-interacting factor (TGIF) and Smad7 in fibroblasts and blocked nuclear translocation of phospho-Smad2. Real-time PCR and immunocytochemistry studies showed that systemic administration of TSA suppressed the inflammation and fibrotic response in the stroma and accelerated epithelial healing in the alkali-burned mouse cornea. Systemic administration of TSA reduces inflammatory and fibrotic responses in the alkali-burned mouse ocular surface in vivo. The mechanisms of action involve attenuation of Smad signal in mesenchymal cells and reduction in the activation and recruitment of macrophages. TSA has the potential to treat corneal scarring in vivo.

Polyclonality of Staphylococcus epidermidis residing on the healthy ocular surface.

PubMed

Ueta, Mayumi; Iida, Tetsuya; Sakamoto, Masako; Sotozono, Chie; Takahashi, Junko; Kojima, Kentaro; Okada, Kazuhisa; Chen, Xiuhao; Kinoshita, Shigeru; Honda, Takeshi

2007-01-01

Staphylococcus epidermidis is part of the normal bacterial flora on the ocular surface. The chromosomal DNA of bacterial isolates obtained from the conjunctival sac, upper and lower lid margins, and upper and lower Meibomian glands of healthy volunteers was subjected to SmaI digestion and PFGE to study the genetic diversity of the organisms. Multiple colonies were also examined of S. epidermidis derived from the conjunctival sac of the same subjects. Lastly, commensal bacteria were harvested from the ocular surfaces of four healthy subjects once a month for 6 months, and the genetic background of the S. epidermidis isolates was analysed. It was found that bacterial strains not only from different subjects but also from multiple ocular surface sites of the same subject exhibited different PFGE patterns. In five of 42 subjects multiple colonies of S. epidermidis were isolated from the conjunctival sac; three harboured multiple colonies with different PFGE patterns, and two manifested multiple colonies with identical PFGE patterns. S. epidermidis isolated from the conjunctival sac of the same subjects over a 6-month period exhibited varying PFGE patterns. The data demonstrate the polyclonality of S. epidermidis on the healthy ocular surface.

Recent Updates on Treatment of Ocular Microbial Infections by Stem Cell Therapy: A Review.

PubMed

Teh, Seoh Wei; Mok, Pooi Ling; Abd Rashid, Munirah; Bastion, Mae-Lynn Catherine; Ibrahim, Normala; Higuchi, Akon; Murugan, Kadarkarai; Mariappan, Rajan; Subbiah, Suresh Kumar

2018-02-13

Ocular microbial infection has emerged as a major public health crisis during the past two decades. A variety of causative agents can cause ocular microbial infections; which are characterized by persistent and destructive inflammation of the ocular tissue; progressive visual disturbance; and may result in loss of visual function in patients if early and effective treatments are not received. The conventional therapeutic approaches to treat vision impairment and blindness resulting from microbial infections involve antimicrobial therapy to eliminate the offending pathogens or in severe cases; by surgical methods and retinal prosthesis replacing of the infected area. In cases where there is concurrent inflammation, once infection is controlled, anti-inflammatory agents are indicated to reduce ocular damage from inflammation which ensues. Despite advances in medical research; progress in the control of ocular microbial infections remains slow. The varying level of ocular tissue recovery in individuals and the incomplete visual functional restoration indicate the chief limitations of current strategies. The development of a more extensive therapy is needed to help in healing to regain vision in patients. Stem cells are multipotent stromal cells that can give rise to a vast variety of cell types following proper differentiation protocol. Stem cell therapy shows promise in reducing inflammation and repairing tissue damage on the eye caused by microbial infections by its ability to modulate immune response and promote tissue regeneration. This article reviews a selected list of common infectious agents affecting the eye; which include fungi; viruses; parasites and bacteria with the aim of discussing the current antimicrobial treatments and the associated therapeutic challenges. We also provide recent updates of the advances in stem cells studies on sepsis therapy as a suggestion of optimum treatment regime for ocular microbial infections.

A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+ T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a “Humanized” HLA Transgenic Rabbit Model

PubMed Central

Srivastava, Ruchi; Khan, Arif A.; Huang, Jiawei; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

2015-01-01

Purpose. A clinical vaccine that protects from ocular herpes simplex virus type 1 (HSV-1) infection and disease still is lacking. In the present study, preclinical vaccine trials of nine asymptomatic (ASYMP) peptides, selected from HSV-1 glycoproteins B (gB), and tegument proteins VP11/12 and VP13/14, were performed in the “humanized” HLA–transgenic rabbit (HLA-Tg rabbit) model of ocular herpes. We recently reported that these peptides are highly recognized by CD8+ T cells from “naturally” protected HSV-1–seropositive healthy ASYMP individuals (who have never had clinical herpes disease). Methods. Mixtures of three ASYMP CD8+ T-cell peptides derived from either HSV-1 gB, VP11/12, or VP13/14 were delivered subcutaneously to different groups of HLA-Tg rabbits (n = 10) in incomplete Freund's adjuvant, twice at 15-day intervals. The frequency and function of HSV-1 epitope-specific CD8+ T cells induced by these peptides and their protective efficacy, in terms of survival, virus replication in the eye, and ocular herpetic disease were assessed after an ocular challenge with HSV-1 (strain McKrae). Results. All mixtures elicited strong and polyfunctional IFN-γ– and TNF-α–producing CD107+CD8+ cytotoxic T cells, associated with a significant reduction in death, ocular herpes infection, and disease (P < 0.015). Conclusions. The results of this preclinical trial support the screening strategy used to select the HSV-1 ASYMP CD8+ T-cell epitopes, emphasize their valuable immunogenic and protective efficacy against ocular herpes, and provide a prototype vaccine formulation that may be highly efficacious for preventing ocular herpes in humans. PMID:26098469

Recent Updates on Treatment of Ocular Microbial Infections by Stem Cell Therapy: A Review

PubMed Central

Teh, Seoh Wei; Mok, Pooi Ling; Abd Rashid, Munirah; Bastion, Mae-Lynn Catherine; Ibrahim, Normala; Higuchi, Akon; Murugan, Kadarkarai; Mariappan, Rajan

2018-01-01

Ocular microbial infection has emerged as a major public health crisis during the past two decades. A variety of causative agents can cause ocular microbial infections; which are characterized by persistent and destructive inflammation of the ocular tissue; progressive visual disturbance; and may result in loss of visual function in patients if early and effective treatments are not received. The conventional therapeutic approaches to treat vision impairment and blindness resulting from microbial infections involve antimicrobial therapy to eliminate the offending pathogens or in severe cases; by surgical methods and retinal prosthesis replacing of the infected area. In cases where there is concurrent inflammation, once infection is controlled, anti-inflammatory agents are indicated to reduce ocular damage from inflammation which ensues. Despite advances in medical research; progress in the control of ocular microbial infections remains slow. The varying level of ocular tissue recovery in individuals and the incomplete visual functional restoration indicate the chief limitations of current strategies. The development of a more extensive therapy is needed to help in healing to regain vision in patients. Stem cells are multipotent stromal cells that can give rise to a vast variety of cell types following proper differentiation protocol. Stem cell therapy shows promise in reducing inflammation and repairing tissue damage on the eye caused by microbial infections by its ability to modulate immune response and promote tissue regeneration. This article reviews a selected list of common infectious agents affecting the eye; which include fungi; viruses; parasites and bacteria with the aim of discussing the current antimicrobial treatments and the associated therapeutic challenges. We also provide recent updates of the advances in stem cells studies on sepsis therapy as a suggestion of optimum treatment regime for ocular microbial infections. PMID:29438279

Contact lens-related dry eye and ocular surface changes with mapping technique in long-term soft silicone hydrogel contact lens wearers.

PubMed

Sengor, Tomris; Aydin Kurna, Sevda; Ozbay, Nurver; Ertek, Semahat; Aki, Suat; Altun, Ahmet

2012-01-01

To evaluate ocular surface changes in long-term silicone hydrogel contact lens wearers. Thirty patients were included in this study. Twenty patients (40 eyes) using contact lenses constituted group 1 and 10 (20 eyes) volunteers constituted group 2. The duration of average contact lens usage was 7.74 ± 3.3 years. Ocular surface was evaluated by surface staining, tear film break-up time (TBUT), Schirmer I test, and conjunctival impression cytology with color-coded mapping technique and by the Ocular Surface Disease Index (OSDI). The mean break-up time was lower and staining scores were higher in group 1 (p<0.001) but Schirmer values were not significantly different from group 2 (p>0.05). The mean OSDI score was 34.59 ± 11.93 to 19.28 ± 6.7 in group 1 and 2. Increased metaplastic predominant changes of grade II and III were observed in the interpalpebral and perilimbal areas in group 1. Significant correlations were observed in TBUT, cornea staining, and grade II to grade III metaplasia ratios between duration of the lens usage and contact lens wear time in a day. Silicone hydrogel lenses produce significant changes on tear film and impression cytology of the ocular surface in long-term use.

Correlation between the histological features of corneal surface pannus following ocular surface burns and the final outcome of cultivated limbal epithelial transplantation.

PubMed

Sati, Alok; Basu, Sayan; Sangwan, Virender S; Vemuganti, Geeta K

2015-04-01

To report the influence of histological features of corneal surface pannus following ocular surface burn on the outcome of cultivated limbal epithelial transplantation (CLET). On retrospectively reviewing the medical records of the patients who underwent autologous CLET from April 2002 to June 2012 at L V Prasad Eye Institute, Hyderabad, India, we could trace the histological reports in only 90 records. These 90 records, besides clinical parameters, were reviewed for the influence of various histological features on the final outcome of CLET. The histological features include epithelial hyperplasia (21.1%), surface ulceration (2.2%), goblet cells (62.2%), squamous metaplasia (11.1%), active fibrosis (31.1%), severe inflammation (8.9%), multinucleated giant cells (3.3%), stromal calcification (8.9%) and active proliferating vessels (5.6%). Among these histological features, patients with either hyperplasia or calcification in their excised corneal pannus show an unfavourable outcome compared with patients without hyperplasia (p=0.003) or calcification (p=0.018). A similar unfavourable outcome was not seen with other histological features and various clinical parameters. Presence of either calcific deposits or hyperplasia in the excised corneal pannus provides poor prognostication; hence, a proper counselling of such patients is mandatory along with a close follow-up. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa.

PubMed

Guffey Johnson, Jean; Terpak, Lauren A; Margo, Curtis E; Setoodeh, Reza

2016-04-01

Low-grade B-cell lymphomas located around the eye present unique challenges in diagnosis and treatment. Extranodal marginal zone B-cell lymphoma is the most common lymphoma of the ocular adnexa (conjunctiva, orbit, lacrimal gland, and eyelid). A systematic search of the relevant literature was performed. Material pertinent to the diagnosis, prognosis, pathogenesis, and treatment of extranodal marginal zone B-cell lymphoma of the ocular adnexa was identified, reviewed, and analyzed, focusing on management strategies for primary localized disease. The primary cause of extranodal marginal zone B-cell lymphoma of the ocular adnexa remains elusive, although an infectious agent is suspected. Radiotherapy is the most common initial treatment for localized disease. Initial treatment with chemotherapy, immunotherapy, and antibiotics has shown promising results, but the number of series is limited and controlled trials do not exist. Although the long-term outcome of localized extranodal marginal zone B-cell lymphoma of the ocular adnexa is good, optimal treatment remains a goal. The variation in rates of local and systemic relapse among treated stage 1E tumors suggests that critical factors affecting outcomes are not fully understood. Radiotherapy is the standard of care; at this time, the evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics for initial treatment of extranodal marginal zone B-cell lymphoma localized to the ocular adnexa. Well-controlled comparative studies are needed.

The contribution of accommodation and the ocular surface to the microfluctuations of wavefront aberrations of the eye.

PubMed

Zhu, Mingxia; Collins, Michael J; Iskander, D Robert

2006-09-01

We have used videokeratoscopy and wavefront sensing to investigate the contribution of the ocular surface and the effect of stimulus vergence on the microfluctuations of the wavefront aberrations of the eye. The fluctuations of the wavefront aberrations were quantified by their variations around the mean and by using power spectrum analysis. Integrated power was determined in two regions: 0.1-0.7 Hz (low frequencies) and 0.8-1.8 Hz (high frequencies). Changes in the ocular surface topography were measured using high-speed videokeratoscopy and variations in the ocular wavefront aberrations were measured with a wavefront sensor. The microfluctuations of wavefront aberrations of the ocular surface were found to be considerably smaller than the microfluctuations of the wavefront aberrations of the total eye. The fluctuations in defocus while viewing a closer target at 2 or 4 D were found to be significantly greater than fluctuations in defocus when viewing a far target. This increase in defocus fluctuations (p < or = 0.001) occurred in both the low- and high-frequency regions of the power spectra.

Application of adipose-derived stem cells on scleral contact lens carrier in an animal model of severe acute alkaline burn.

PubMed

Espandar, Ladan; Caldwell, Delmar; Watson, Richard; Blanco-Mezquita, Tomas; Zhang, Shijia; Bunnell, Bruce

2014-07-01

To evaluate the therapeutic effect of human adipose-derived stem cells (hASCs) overlaid on a scleral contact lens (SCL) carrier in a rabbit model of ocular alkaline burn. After inducing alkaline burn in 11 New Zealand white rabbits, hASCs cultured on SCLs were placed on the right eye of 5 rabbits, SCLs without cells were used in 5, and no treatment was applied in 1 eye. Each eye was examined and photographed for corneal vascularization, opacities, and epithelial defect in week 1, 2, and 4 after surgery. After 1 month, rabbits were killed and the corneas were removed and cut in half for electron and light microscopy examination. Human adipose-derived stem cells were attached to SCL surface and confluent easily. Human adipose-derived stem cells on SCL eyes showed smaller epithelial defect, less corneal opacity, corneal neovascularization relative to SCL eyes. Both groups showed no symblepharon. However, the cornea in the untreated eye was melted in 2 weeks and developed severe symblepharon. Human adipose-derived stem cells on SCL can reduce inflammation and corneal haziness in severe ocular alkaline burn injury in rabbits.

Application of Adipose-Derived Stem Cells on Scleral Contact Lens Carrier in an Animal Model of Severe Acute Alkaline Burn

PubMed Central

Espandar, Ladan; Caldwell, Delmar; Watson, Richard; Blanco-Mezquita, Tomas; Zhang, Shijia; Bunnell, Bruce

2015-01-01

Purpose To evaluate the therapeutic effect of human adipose-derived stem cells (hASCs) overlaid on a scleral contact lens (SCL) carrier in a rabbit model of ocular alkaline burn. Materials and Methods After inducing alkaline burn in 11 New Zealand white rabbits, hASCs cultured on SCLs were placed on the right eye of 5 rabbits, SCLs without cells were used in 5, and no treatment was applied in 1 eye. Each eye was examined and photographed for corneal vascularization, opacities, and epithelial defect in week 1, 2, and 4 after surgery. After 1 month, rabbits were killed and the corneas were removed and cut in half for electron and light microscopy examination. Results Human adipose-derived stem cells were attached to SCL surface and confluent easily. Human adipose-derived stem cells on SCL eyes showed smaller epithelial defect, less corneal opacity, corneal neovascularization relative to SCL eyes. Both groups showed no symblepharon. However, the cornea in the untreated eye was melted in 2 weeks and developed severe symblepharon. Conclusion Human adipose-derived stem cells on SCL can reduce inflammation and corneal haziness in severe ocular alkaline burn injury in rabbits. PMID:24901976

Ex vivo enrichment of circulating anti-tumor T cells from both cutaneous and ocular melanoma patients: clinical implications for adoptive cell transfer therapy.

PubMed

Mazzarella, Tonia; Cambiaghi, Valeria; Rizzo, Nathalie; Pilla, Lorenzo; Parolini, Danilo; Orsenigo, Elena; Colucci, Annalisa; Modorati, Giulio; Doglioni, Claudio; Parmiani, Giorgio; Maccalli, Cristina

2012-08-01

Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally differentiated T(EM) cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients.

Development of novel encapsulated formulations using albumin-chitosan as a polymer matrix for ocular drug delivery

NASA Astrophysics Data System (ADS)

Addo, Richard Tettey

Designing formulations for ophthalmic drug delivery is one of the most challenging endeavors facing the pharmaceutical scientist due to the unique anatomy, physiology, and biochemistry of the eye. Current treatment protocols for administration of drugs in eye diseases are primarily solution formulations, gels or ointments. However, these modes of delivery have several drawbacks such as short duration of exposure, need for repeated administrations and non-specific toxicity. We hypothesize that development of ocular drugs in microparticles will overcome the deficiencies of the current modalities of treatment. We based the hypothesis on the preliminary studies conducted with encapsulated tetracaine, an anesthetic used for surgical purposes and atropine, a medication used for several ophthalmic indications including mydriatic and cycloplegic effects. However, atropine is well absorbed into the systemic circulation and has been reported to exert severe systemic side effects after ocular administration (Hoefnagel D. 1961, Morton H. G. 1939 and Lang J. C. 1995) and may lead to serious side effects including death in extreme cases with pediatric use. Based on these observations, the focus of this dissertation is to formulate microparticulate drug carrier for treatment of various conditions of the eye. Purpose: To prepare, characterize, study the in vitro and in vivo interaction of albumin-chitosan microparticles (BSA-CSN MS), a novel particulate drug carrier for ocular drug delivery. Method: Microparticle formulations were prepared by method of spray drying. The percentage drug loading and efficiency were assessed using USP (I) dissolution apparatus. Using Malvern Zeta-Sizer, we determined size and surface charge of the fabrication. Surface morphology of the microparticles was examined using Scanning Electron Microscopy. Microparticles were characterized in terms of thermal properties using Differential Scanning Calorimetry. Human corneal epithelial cells (HCET-1) were exposed up to 120 minutes to different BSA-CSN MS concentrations. Using fluorometry, the influence of temperature and effect of metabolic inhibition were studied. The in vitro uptake and internalization studies were evaluated using confocal microscopy in HCET-1. In vivo studies were evaluated in rabbit's eye using blink response and pupil to cornea ratio for tetracaine and atropine studies respectively. Results: Our results showed particles size in the range of 3-5 microns with encapsulation efficiency of about 96 percent. Differential Scanning Calorimetry showed no drug-polymer interactions. BSA-CSN MS were internalized by the HCET-1 and was affected both by temperature and metabolic inhibitor, sodium azide. There were no signs of ocular surface toxicity or inflammation. The encapsulated drugs exhibited superior properties in vivo compared to the solution formulations currently in clinical use. Conclusion: We successfully developed microparticulate drug carriers for ocular delivery. BSA-CSN MS were internalized by the HCET-1 by temperature dependent active transport mechanism that did not compromise cell viability.

Dextran and protamine-based solid lipid nanoparticles as potential vectors for the treatment of X-linked juvenile retinoschisis.

PubMed

Delgado, Diego; del Pozo-Rodríguez, Ana; Solinís, Maria Ángeles; Avilés-Triqueros, Marcelino; Weber, Bernhard H F; Fernández, Eduardo; Gascón, Alicia R

2012-04-01

The goal of the present study was to analyze the potential application of nonviral vectors based on solid lipid nanoparticles (SLN) for the treatment of ocular diseases by gene therapy, specifically X-linked juvenile retinoschisis (XLRS). Vectors were prepared with SLN, dextran, protamine, and a plasmid (pCMS-EGFP or pCEP4-RS1). Formulations were characterized and the in vitro transfection capacity as well as the cellular uptake and the intracellular trafficking were studied in ARPE-19 cells. Formulations were also tested in vivo in Wistar rat eyes, and the efficacy was studied by monitoring the expression of enhanced green fluorescent protein (EGFP) after intravitreal, subretinal, and topical administration. The presence of dextran and protamine in the SLN improved greatly the expression of retinoschisin and EGFP in ARPE-19 cells. The nuclear localization signals of protamine, its ability to protect the DNA, and a shift in the entry mechanism from caveola-mediated to clathrin-mediated endocytosis promoted by the dextran, justify the increase in transfection. After ocular administration of the dextran-protamine-DNA-SLN complex to rat eyes, we detected the expression of EGFP in various types of cells depending on the administration route. Our vectors were also able to transfect corneal cells after topical application. We have demonstrated the potential usefulness of our nonviral vectors loaded with XLRS1 plasmid and provided evidence for their potential application for the management or treatment of degenerative retinal disorders as well as ocular surface diseases.

Virulence properties of multidrug resistant ocular isolates of Acinetobacter baumannii.

PubMed

Talreja, Deepa; Muraleedharan, Chithra; Gunathilaka, Gayathri; Zhang, Yifan; Kaye, Keith S; Walia, Satish K; Kumar, Ashok

2014-07-01

Acinetobacter (A.) baumannii is an opportunistic pathogen and has been reported as a causative agent of ocular infections. The aim of this study is to identify virulence properties (biofilm formation, adhesion, invasion and cytotoxicity) and antibiotic resistance among A. baumannii isolates recovered from the eye. The Microscan Walk-Away®, an automated bacterial identification and susceptibility testing system was used to determine antibiotic resistance. Clonal relatedness was assessed by Pulsed-field gel electrophoresis (PFGE) and plasmid profile analysis. Conjugation experiments were carried out to determine the transfer of antibiotic resistance genes and PCR was used to confirm gene transfer. Virulence properties of the isolates were determined by biofilm formation using crystal violet and immunofluorescence staining, adherence and internalization using cultured corneal epithelial cells, and cytotoxicity by TUNEL-staining and LDH release assays. All ocular isolates (n = 12) exhibited multidrug resistant (MDR) phenotype and one of the isolate (AB12) was resistant to 18 antibiotics (β-lactam, aminoglycosides, tetracycline, chloramphenicol and quinolones). The plasmid profile analysis showed the presence of multiple plasmids in each isolate and a total of 10 different profiles were observed. However, PFGE analysis was more discriminatory which revealed 12 distinct genotypes. Antibiotic resistance (tetracycline and quinolone) was transferable from the isolate AB12 to a recipient Escherichia coli J53. Ten isolates were strong biofilm producers and the remaining two (AB5 and AB7) were moderate producers. All isolates demonstrated adherence and invasive properties towards HCECs. A similar trend was observed in their ability to cause cell death and toxicity. Our results indicate that ocular isolates of A. baumannii are biofilm producers and adherent and invasive to corneal epithelium, a first step in the pathogenesis of ocular infection. In addition, they demonstrated plasmid-mediated transfer of MDR traits making them a reservoir of resistance genes at ocular surface.

Effect of pro-inflammatory mediators on membrane-associated mucins expressed by human ocular surface epithelial cells.

PubMed

Albertsmeyer, Ann-Christin; Kakkassery, Vinodh; Spurr-Michaud, Sandra; Beeks, Olivia; Gipson, Ilene K

2010-03-01

Membrane-associated mucins are altered on the ocular surface in non-Sjögren's dry eye. This study sought to determine if inflammatory mediators, present in tears of dry eye patients, regulate membrane-associated mucins MUC1 and -16 at the level of gene expression, protein biosynthesis and/or ectodomain release. A human corneal limbal epithelial cell line (HCLE), which produces membrane-associated mucins, was used. Cells were treated with interleukin (IL)-6, -8, or -17, tumor necrosis factor-alpha (TNF-alpha), and Interferon-gamma (IFN-gamma), or a combination of TNF-alpha and IFN-gamma, or IFN-gamma and IL-17, for 1, 6, 24, or 48 h. Presence of receptors for these mediators was verified by RT-PCR. Effects of the cytokines on expression levels of MUC1 and -16 were determined by real-time PCR, and on mucin protein biosynthesis and ectodomain release in cell lysates and culture media, respectively, by immunoblot analysis. TNF-alpha and IFN-gamma each significantly induced MUC1 expression, cellular protein content and ectodomain release over time. Combined treatment with the two cytokines was not additive. By comparison, one of the inflammatory mediators, IFN-gamma, affected all three parameters-gene expression, cellular protein, and ectodomain release-for MUC16. Combined treatment with TNF-alpha and IFN-gamma showed effects similar to IFN-gamma alone, except that ectodomain release followed that of TNF-alpha, which induced MUC16 ectodomain release. In conclusion, inflammatory mediators present in tears of dry eye patients can affect MUC1 and -16 on corneal epithelial cells and may be responsible for alterations of surface mucins in dry eye.

Hyaluronan receptors in the human ocular surface: a descriptive and comparative study of RHAMM and CD44 in tissues, cell lines and freshly collected samples.

PubMed

García-Posadas, Laura; Contreras-Ruiz, Laura; López-García, Antonio; Villarón Álvarez, Sonia; Maldonado, Miguel J; Diebold, Yolanda

2012-02-01

The purpose of this study was to demonstrate the presence of the receptor for hyaluronan-mediated motility (RHAMM) in human conjunctival epithelium and in two widely used cell lines from human corneal (HCE) and conjunctival (IOBA-NHC) epithelia. We compared the distribution of RHAMM proteins and mRNAs in human ocular surface tissues (corneal, limbal and conjunctival), HCE and IOBA-NHC cell lines, and corneal and conjunctival epithelia primary samples from healthy donors with the previously identified hyaluronan receptor CD44. We also aimed to determine if soluble CD44 (sCD44) was present in human tears, as it could have a role in the interaction of the tear fluid with hyaluronan. Protein expression was evaluated by Western blots and immunofluorescence microscopy. mRNA expression was evaluated by RT-PCR and Q-PCR. sCD44 was analyzed by ELISA in culture supernatants and in human tears. We describe the expression of RHAMM in human healthy conjunctiva and in HCE and IOBA-NHC cells at both protein and mRNA levels, and the presence of sCD44 in human tears. Furthermore, we detected CD44 and sCD44 expression variations in in vitro inflammatory conditions. This study also focused on the necessary caution with which the conclusions extracted from cell lines should be made, and in the great value of using primary samples as often as possible.

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

PubMed Central

Arakaki, Rieko; Eguchi, Hiroshi; Yamada, Akiko; Kudo, Yasusei; Iwasa, Akihiko; Enkhmaa, Tserennadmid; Hotta, Fumika; Mitamura-Aizawa, Sayaka; Mitamura, Yoshinori; Hayashi, Yoshio; Ishimaru, Naozumi

2014-01-01

Background Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown. Methods and Finding Reb eyedrops were administered to the murine model of SS aged 4–8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment. Conclusion Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces. PMID:24866156

The Effects of Increasing Ocular Surface Stimulation on Blinking and Tear Secretion

PubMed Central

Wu, Ziwei; Begley, Carolyn G.; Port, Nicholas; Bradley, Arthur; Braun, Richard; King-Smith, Ewen

2015-01-01

Purpose. To investigate the effect of varying levels of ocular surface stimulation on the timing and amplitude of the blink and tear secretion. Methods. Following instillation of fluorescein dye, increasing levels of air flow were directed toward the central corneas of 10 healthy subjects. Interblink interval (IBI), tear meniscus height (TMH), and fluorescence intensity were measured simultaneously. Because blinking can obscure changes in TMH, we developed novel measures of tear secretion by calculating tear meniscus fluorescein concentration (TMFC) from intensity using a mathematical model. The change of TMH and TMFC over trials and the slope of the TMFC within each IBI (IBI-TTR) were further calculated. Results. The mean IBI was decreased by 8.08 ± 8.54 seconds from baseline to maximum air stimulation. The TMH increase was highly variable (0.41 ± 0.39 mm) among subjects, compared to the fluorescence tear turnover metrics: decrease in TMFC of 2.84 ± 0.98 natural logarithm or ln(%) and IBI-TTR of 0.065 ± 0.032 ln(%)/sec. Ocular surface stimulation was highly correlated with the TMFC and IBI-TTR, but less so with TMH (Pearson's r = 0.71, 0.69, and 0.40, P < 0.01, respectively). Blinking and tearing were significantly correlated with each other (Pearson's r = 0.56, P < 0.01), but tearing lagged behind by an average of 6.54 ± 4.07 seconds. Conclusions. Blinking and tearing share a common origin with sensory stimulation at the ocular surface. Both showed a dose–response increase with surface stimulation and were correlated with each other. These methods can potentially be used to understand alterations in ocular surface sensory function and associated protective responses in dry eye and other disorders of the ocular surface. PMID:26132780

The Effects of Increasing Ocular Surface Stimulation on Blinking and Tear Secretion.

PubMed

Wu, Ziwei; Begley, Carolyn G; Port, Nicholas; Bradley, Arthur; Braun, Richard; King-Smith, Ewen

2015-07-01

To investigate the effect of varying levels of ocular surface stimulation on the timing and amplitude of the blink and tear secretion. Following instillation of fluorescein dye, increasing levels of air flow were directed toward the central corneas of 10 healthy subjects. Interblink interval (IBI), tear meniscus height (TMH), and fluorescence intensity were measured simultaneously. Because blinking can obscure changes in TMH, we developed novel measures of tear secretion by calculating tear meniscus fluorescein concentration (TMFC) from intensity using a mathematical model. The change of TMH and TMFC over trials and the slope of the TMFC within each IBI (IBI-TTR) were further calculated. The mean IBI was decreased by 8.08 ± 8.54 seconds from baseline to maximum air stimulation. The TMH increase was highly variable (0.41 ± 0.39 mm) among subjects, compared to the fluorescence tear turnover metrics: decrease in TMFC of 2.84 ± 0.98 natural logarithm or ln(%) and IBI-TTR of 0.065 ± 0.032 ln(%)/sec. Ocular surface stimulation was highly correlated with the TMFC and IBI-TTR, but less so with TMH (Pearson's r = 0.71, 0.69, and 0.40, P < 0.01, respectively). Blinking and tearing were significantly correlated with each other (Pearson's r = 0.56, P < 0.01), but tearing lagged behind by an average of 6.54 ± 4.07 seconds. Blinking and tearing share a common origin with sensory stimulation at the ocular surface. Both showed a dose-response increase with surface stimulation and were correlated with each other. These methods can potentially be used to understand alterations in ocular surface sensory function and associated protective responses in dry eye and other disorders of the ocular surface.

Itchy-dry eye associated with polycystic ovary syndrome.

PubMed

Bonini, Stefano; Mantelli, Flavio; Moretti, Costanzo; Lambiase, Alessandro; Bonini, Sergio; Micera, Alessandra

2007-05-01

The authors aimed to define the ocular symptomatology of women with polycystic ovaries and hyperandrogenism. Prospective, observational case series. Of the 62 consecutive patients with an ultrasonographic diagnosis of polycystic ovary (PCO), 16 were identified as having clinical and biochemical signs of hyperandrogenism. All women with a history of ocular symptoms (20/62 total patients [32.3%], 15/16 polycystic ovary syndrome (PCOS) patients [93.7%], and 5/46 PCO patients [10.8%]) underwent a complete eye examination with conjunctival impression cytologic sampling. Clinical measurements of tear function (tear film break-up time [BUT], Schirmer I test) were completed along with analysis of conjunctival goblet cell number, conjunctival immunostaining, and reverse-transcriptase polymerase chain reaction for the mucins MUC1 and MUC5AC. Clinical, histologic, and biochemical data of patients with PCOS were compared statistically with that of patients with PCO and with eight age- and gender-matched healthy controls. Eight of the most severely affected patients received systemic antiandrogen therapy and underwent further ocular evaluation four months after systemic therapy. Women with PCOS had greater conjunctival hyperemia (P < .001), dryness (P < .001), itching (P < .001), mucous discharge (P < .001), and contact lens intolerance (P < .001) than patients with PCO. Patients with PCOS had a significant reduction of the tear film BUT accompanied by a significant increase in goblet cell number and conjunctival MUC5AC messenger ribonucleic acid expression compared with both PCO patients and healthy subjects. Evaluation of the ocular surface should be considered in patients with PCO or PCOS. Women with PCOS were more likely to have itchy-dry eyes, decreased tear film BUT, and increased goblet cell density.

The TFOS International Workshop on Contact Lens Discomfort: Report of the Subcommittee on Neurobiology

PubMed Central

Stapleton, Fiona; Marfurt, Carl; Golebiowski, Blanka; Rosenblatt, Mark; Bereiter, David; Begley, Carolyn; Dartt, Darlene; Gallar, Juana; Belmonte, Carlos; Hamrah, Pedram; Willcox, Mark

2013-01-01

This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens–related discomfort. While there is limited evidence for the mechanisms involved in contact lens–related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation. Sensory input will arise from stimulation of the lid margin, palpebral and bulbar conjunctiva, and the cornea. PMID:24058137

Isolation of the ocular surface to treat dysfunctional tear syndrome associated with computer use.

PubMed

Yee, Richard W; Sperling, Harry G; Kattek, Ashballa; Paukert, Martin T; Dawson, Kevin; Garcia, Marcie; Hilsenbeck, Susan

2007-10-01

Dysfunctional tear syndrome (DTS) associated with computer use is characterized by mild irritation, itching, redness, and intermittent tearing after extended staring. It frequently involves foreign body or sandy sensation, blurring of vision, and fatigue, worsening especially at the end of the day. We undertook a study to determine the effectiveness of periocular isolation using microenvironment glasses (MEGS) alone and in combination with artificial tears in alleviating the symptoms and signs of dry eye related to computer use. At the same time, we evaluated the relative ability of a battery of clinical tests for dry eye to distinguish dry eyes from normal eyes in heavy computer users. Forty adult subjects who used computers 3 hours or more per day were divided into dry eye sufferers and controls based on their scores on the Ocular Surface Disease Index (OSDI). Baseline scores were recorded and ocular surface assessments were made. On four subsequent visits, the subjects played a computer game for 30 minutes in a controlled environment, during which one of four treatment conditions were applied, in random order, to each subject: 1) no treatment, 2) artificial tears, 3) MEGS, and 4) artificial tears combined with MEGS. Immediately after each session, subjects were tested on: a subjective comfort questionnaire, tear breakup time (TBUT), fluorescein staining, lissamine green staining, and conjunctival injection. In this study, a significant correlation was found between cumulative lifetime computer use and ocular surface disorder, as measured by the standardized OSDI index. The experimental and control subjects were significantly different (P<0.05) in the meibomian gland assessment and TBUT; they were consistently different in fluorescein and lissamine green staining, but with P>0.05. Isolation of the ocular surface alone produced significant improvements in comfort scores and TBUT and a consistent trend of improvement in fluorescein staining and lissamine green staining. Isolation plus tears produced a significant improvement in lissamine green staining. The subjective comfort inventory and the TBUT test were most effective in distinguishing between the treatments used. Computer users with ocular surface complaints should have a detailed ocular surface examination and, if symptomatic, they can be effectively treated with isolation of the ocular surface, artificial tears therapy, and effective environmental manipulations.

Uveitis as an initial manifestation of acquired immunodeficiency syndrome.

PubMed

Tsen, Chui-Lien; Chen, Shih-Chou; Chen, Yao-Shen; Sheu, Shwu-Jiuan

2017-10-01

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a multisystem disease that can involve the human eyes. Using ophthalmic examination records from January 2006 to November 2015, we retrospectively reviewed all patients who were diagnosed with HIV/AIDS in our hospital. The study was performed at a tertiary referral center in southern Taiwan. Data included age, gender, ophthalmic examinations, systemic conditions, CD4 cell counts, course, and treatment. Eleven patients were identified as having AIDS with uveitis as their presenting manifestation. All were men, with a mean age of 39.5 ± 11.4 years (range 24-56). The mean CD4 + T-cell counts were 91.7 ± 50.3 cells/μl (range 27-169). Ocular diagnoses included cytomegalovirus (CMV) retinitis in five patients, ocular syphilis in four patients, and ocular toxoplasmosis in two patients. Uveitis resolved in all patients after medical treatment. However, a retinal detachment developed in two eyes in CMV retinitis and one eye in ocular syphilis. Ocular manifestations are among the most common clinical features in patients with HIV/AIDS who have varying clinical presentations that affect almost all ocular structures. This study demonstrated that ocular findings could be an initial manifestation of an underlying disease. Awareness of ocular lesions in HIV/AIDS is important for early recognition and management.

Antibacterial activity of dilute povidone-iodine solutions used for ocular surface disinfection in dogs.

PubMed

Roberts, S M; Severin, G A; Lavach, J D

1986-06-01

Bacterial cultures of specimens from healthy canine eyelids and ocular surfaces were found to demonstrate bacterial growth in 69.7% (53/76) of the eyes sampled. Organisms most commonly isolated included: Staphylococcus aureus, alpha-hemolytic Streptococcus sp, S epidermidis, and Escherichia coli. Evaluation of dilute povidone-iodine solutions for effectiveness as ocular surface disinfectants was conducted. Bacterial growth initially detected in 32 of 46 eyes was not detected after disinfection with a 2-minute scrub and 2-minute soaking procedure, using 1:2, 1:10, or 1:50 dilutions of a povidone-iodine solution that contained 1% available iodine. The eyelid and ocular surfaces of 16 eyes were disinfected with 1:100 povidone-iodine solution. Bacterial growth initially present in 10 of 16 eyes was present in 1 eye after disinfection and consisted of a single colony of E coli. After eyes were disinfected with 1:10, 1:50, or 1:100 povidone-iodine solutions, there was no evidence of corneal epithelial edema or sloughing. In 15 eyes subjected to disinfection with the 1:2 dilution, one instance of epithelial corneal edema was noticed. A 1:50 dilution of povidone-iodine is recommended as an ocular surface disinfectant for use in presurgical situations.

Adaptive Neuromorphic Circuit for Stereoscopic Disparity Using Ocular Dominance Map

PubMed Central

Sharma, Sheena; Gupta, Priti; Markan, C. M.

2016-01-01

Stereopsis or depth perception is a critical aspect of information processing in the brain and is computed from the positional shift or disparity between the images seen by the two eyes. Various algorithms and their hardware implementation that compute disparity in real time have been proposed; however, most of them compute disparity through complex mathematical calculations that are difficult to realize in hardware and are biologically unrealistic. The brain presumably uses simpler methods to extract depth information from the environment and hence newer methodologies that could perform stereopsis with brain like elegance need to be explored. This paper proposes an innovative aVLSI design that leverages the columnar organization of ocular dominance in the brain and uses time-staggered Winner Take All (ts-WTA) to adaptively create disparity tuned cells. Physiological findings support the presence of disparity cells in the visual cortex and show that these cells surface as a result of binocular stimulation received after birth. Therefore, creating in hardware cells that can learn different disparities with experience not only is novel but also is biologically more realistic. These disparity cells, when allowed to interact diffusively on a larger scale, can be used to adaptively create stable topological disparity maps in silicon. PMID:27243029

Presumed post-traumatic ocular chondrosarcoma with intrathoracic metastases in a cat.

PubMed

Moreira, Matheus V L; de Andrade, Maria C; Fulgêncio, Gustavo O; Langohr, Ingeborg M; Ecco, Roselene

2017-10-03

An indoor-only, 5-year-old, spayed female domestic shorthair cat presented for an ophthalmic examination of the left eye. An intraocular tumor with secondary glaucoma and blindness was diagnosed; the globe was enucleated and sent for histopathological examination. Gross examination revealed a solid white mass filling the entire vitreous space and replacing the iris and ciliary body. The lens and retina appeared to be similarly replaced by the neoplasm. Histological examination revealed a complete loss of the internal ocular structures, with a ruptured capsule as the only remnant of the lens within an extensive malignant mesenchymal neoplastic cell proliferation. The cells were polygonal, with well-defined cytoplasmic borders and abundant weakly basophilic cytoplasm, embedded within the islands of chondroid matrix. No neoplastic invasion of the sclera was apparent. The animal died 6 months after the enucleation due to respiratory distress. Gross examination revealed numerous firm, white to tan nodular masses with smooth to mildly irregular surfaces dispersed throughout the parietal pleura, thoracic surface of the diaphragm, tracheobronchial and mediastinal lymph nodes, pericardium, and lungs. On cross-section, the neoplastic nodules were solid and variably translucent, resembling hyaline cartilage. Histologically, these nodules were similar to the neoplasm identified earlier in the left globe. Metastasis of post-traumatic ocular chondrosarcoma has not yet been described in cats. This is therefore believed to be the first report of metastases of this type of neoplasm in cats. This case adds to the limited set of data on the outcome of this type of tumor. © 2017 American College of Veterinary Ophthalmologists.

Cytotoxicity and genotoxicity of bacterial magnetosomes against human retinal pigment epithelium cells

NASA Astrophysics Data System (ADS)

Qi, Lei; Lv, Xiujuan; Zhang, Tongwei; Jia, Peina; Yan, Ruiying; Li, Shuli; Zou, Ruitao; Xue, Yuhua; Dai, Liming

2016-06-01

A variety of nanomaterials have been developed for ocular diseases. The ability of these nanomaterials to pass through the blood-ocular barrier and their biocompatibility are essential characteristics that must be considered. Bacterial magnetosomes (BMs) are a type of biogenic magnetic nanomaterials synthesized by magnetotactic bacteria. Due to their unique biomolecular membrane shell and narrow size distribution of approximately 30 nm, BMs can pass through the blood-brain barrier. The similarity of the blood-ocular barrier to the blood-brain barrier suggests that BMs have great potential as treatments for ocular diseases. In this work, BMs were isolated from magnetotactic bacteria and evaluated in various cytotoxicity and genotoxicity studies in human retinal pigment epithelium (ARPE-19) cells. The BMs entered ARPE-19 cells by endocytosis after a 6-h incubation and displayed much lower cytotoxicity than chemically synthesized magnetic nanoparticles (MNPs). MNPs exhibited significantly higher genotoxicity than BMs and promoted the expression of Bax (the programmed cell death acceleration protein) and the induction of greater cell necrosis. In BM-treated cells, apoptosis tended to be suppressed via increased expression of the Bcl-2 protein. In conclusion, BMs display excellent biocompatibility and potential for use in the treatment of ocular diseases.

Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection.

PubMed

Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang; Mahdi, Rashid M; Shen, De Fen; Chan, Chi-Chao; Egwuagu, Charles E

2015-04-01

Immunological responses to pathogens are stringently regulated in the eye to prevent excessive inflammation that damage ocular tissues and compromise vision. Suppressors of cytokine signaling (SOCS) regulate intensity/duration of inflammatory responses. We have used SOCS1-deficient mice and retina-specific SOCS1 transgenic rats to investigate roles of SOCS1 in ocular herpes simplex virus (HSV-1) infection and non-infectious uveitis. We also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and examined whether they can be used to inhibit inflammatory cytokines. Overexpression of SOCS1 in transgenic rat eyes attenuated ocular HSV-1 infection while SOCS1-deficient mice developed severe non-infectious anterior uveitis, suggesting that SOCS1 may contribute to mechanism of ocular immune privilege by regulating trafficking of inflammatory cells into ocular tissues. Furthermore, MTS-SOCS1 inhibited IFN-γ-induced signal transducers and activators of transcription 1 (STAT1) activation by macrophages while MTS-SOCS3 suppressed expansion of pathogenic Th17 cells that mediate uveitis, indicating that MTS-SOCS proteins maybe used to treat ocular inflammatory diseases of infectious or autoimmune etiology.

Distribution of CD163-positive cell and MHC class II-positive cell in the normal equine uveal tract.

PubMed

Sano, Yuto; Matsuda, Kazuya; Okamoto, Minoru; Takehana, Kazushige; Hirayama, Kazuko; Taniyama, Hiroyuki

2016-02-01

Antigen-presenting cells (APCs) in the uveal tract participate in ocular immunity including immune homeostasis and the pathogenesis of uveitis. In horses, although uveitis is the most common ocular disorder, little is known about ocular immunity, such as the distribution of APCs. In this study, we investigated the distribution of CD163-positive and MHC II-positive cells in the normal equine uveal tract using an immunofluorescence technique. Eleven eyes from 10 Thoroughbred horses aged 1 to 24 years old were used. Indirect immunofluorescence was performed using the primary antibodies CD163, MHC class II (MHC II) and CD20. To demonstrate the site of their greatest distribution, positive cells were manually counted in 3 different parts of the uveal tract (ciliary body, iris and choroid), and their average number was assessed by statistical analysis. The distribution of pleomorphic CD163- and MHC II-expressed cells was detected throughout the equine uveal tract, but no CD20-expressed cells were detected. The statistical analysis demonstrated the distribution of CD163- and MHC II-positive cells focusing on the ciliary body. These results demonstrated that the ciliary body is the largest site of their distribution in the normal equine uveal tract, and the ciliary body is considered to play important roles in uveal and/or ocular immune homeostasis. The data provided in this study will help further understanding of equine ocular immunity in the normal state and might be beneficial for understanding of mechanisms of ocular disorders, such as equine uveitis.

Therapeutic inhibitors for the treatment of dry eye syndrome.

PubMed

Rodríguez-Pomar, Candela; Pintor, Jesus; Colligris, Basilio; Carracedo, Gonzalo

2017-12-01

Dry eye disease (DED), defined as a multifactorial disease of tears and ocular surface, results in symptoms of discomfort, ocular irritation, visual disturbance and tear film instability. This syndrome is accompanied of ocular surface inflammation and it is produced by a deficient activity of the lacrimal functional unit. In addition, it is associated with systemic autoimmune diseases such as Sjögren´s Syndrome, rheumatoid arthritis, systemic lupus erythematosus and some drug administration. The treatment of dry eye disease is based on the typical signs and symptoms of dry eye, which are associated with hyperosmolarity, ocular surface inflammation, discomfort, visual disturbance, and tear film instability. Areas covered: This review is focused on synthetic drugs currently used in clinical practice, from phase III development onwards to treat the ocular surface signs and symptoms of dry eye disease. Expert opinion: The multifactorial disease and the lack of correlation between signs and symptoms imply that not all the pharmacological approaches will be successful for dry eye. The correct design of the clinical trials, with appropriate endpoints, and the type of dry eye under study are complicated but mandatory. The anti-inflammatory and secretagogues drugs are both the main compounds to currently treat the dry eye disease.

Platelet lysate and chondroitin sulfate loaded contact lenses to heal corneal lesions.

PubMed

Sandri, Giuseppina; Bonferoni, Maria Cristina; Rossi, Silvia; Delfino, Alessio; Riva, Federica; Icaro Cornaglia, Antonia; Marrubini, Giorgio; Musitelli, Giorgio; Del Fante, Claudia; Perotti, Cesare; Caramella, Carla; Ferrari, Franca

2016-07-25

Hemoderivative tear substitutes contain various ephiteliotrophic factors, such as growth factors (GF), involved in ocular surface homeostasis without immunogenic properties. The aim of the present work was the loading of platelet lysate into contact lenses to improve the precorneal permanence of platelet lysate growth factors on the ocular surface to enhance the treatment of corneal lesions. To this purpose, chondroitin sulfate, a sulfated glycosaminoglycan, which is normally present in the extracellular matrix, was associated with platelet lysate. In fact, chondroitin sulfate is capable of electrostatic interaction with positively charged growth factors, in particular, with bFGF, IGF, VEGF, PDGF and TGF-β, resulting in their stabilization and reduced degradation in solution. In the present work, various types of commercially available contact lenses have been loaded with chondroitin sulfate or chondroitin sulfate in association with platelet lysate to achieve a release of growth factors directly onto the corneal surface lesions. One type of contact lenses (PureVision(®)) showed in vitro good proliferation properties towards corneal cells and were able to enhance cut closure in cornea constructs. Copyright © 2016 Elsevier B.V. All rights reserved.

Ocular Surface Symptoms in Veterans Returning From Operation Iraqi Freedom and Operation Enduring Freedom

PubMed Central

Modi, Yasha S.; Qurban, Qirat; Zlotcavitch, Leonid; Echeverri, Roberto J.; Feuer, William; Florez, Hermes; Galor, Anat

2014-01-01

Purpose. To correlate situational exposures and psychiatric disease with self-reported ocular surface symptoms in a younger veteran population involved in Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF). Methods. Cross-sectional study of all veterans evaluated in the OIF/OEF clinic between December 2012 and April 2013 who completed the dry eye questionnaire and screening evaluations for environmental exposures, posttraumatic stress disorder (PTSD), and depression. The main outcome measures were the influence of environmental exposure and psychiatric disease on ocular surface symptoms. Results. Of 115 participants, the average age was 33 years. While overseas, exposure to incinerated waste (odds ratio [OR] 2.67, 95% confidence interval [CI] 1.23–5.81, P = 0.02) and PTSD (OR 2.68, 95% CI 1.23–5.85, P = 0.02) were associated with self-reported ocular surface symptoms. On return to the United States, older age (OR per decade 2.66, 95% CI 1.65–4.31, P = 0.04) was associated with persistent symptoms and incinerated waste was associated with resolution of symptoms (OR 0.25, 95% CI 0.07–0.90, P = 0.04). When evaluating symptom severity, 26% of the responders complained of severe ocular surface symptoms, with PTSD (OR 3.10, 95% CI 1.22–7.88, P = 0.02) and depression (OR 4.28, 95% CI 1.71–10.68, P = 0.002) being significant risk factors for their presence. Conclusions. PTSD was significantly associated with ocular surface symptoms both abroad and on return to the United States, whereas air pollution in the form of incinerated waste, was correlated with reversible symptoms. PMID:24408975

Clinical evaluation of accommodation and ocular surface stability relavant to visual asthenopia with 3D displays

PubMed Central

2014-01-01

Background To validate the association between accommodation and visual asthenopia by measuring objective accommodative amplitude with the Optical Quality Analysis System (OQAS®, Visiometrics, Terrassa, Spain), and to investigate associations among accommodation, ocular surface instability, and visual asthenopia while viewing 3D displays. Methods Fifteen normal adults without any ocular disease or surgical history watched the same 3D and 2D displays for 30 minutes. Accommodative ability, ocular protection index (OPI), and total ocular symptom scores were evaluated before and after viewing the 3D and 2D displays. Accommodative ability was evaluated by the near point of accommodation (NPA) and OQAS to ensure reliability. The OPI was calculated by dividing the tear breakup time (TBUT) by the interblink interval (IBI). The changes in accommodative ability, OPI, and total ocular symptom scores after viewing 3D and 2D displays were evaluated. Results Accommodative ability evaluated by NPA and OQAS, OPI, and total ocular symptom scores changed significantly after 3D viewing (p = 0.005, 0.003, 0.006, and 0.003, respectively), but yielded no difference after 2D viewing. The objective measurement by OQAS verified the decrease of accommodative ability while viewing 3D displays. The change of NPA, OPI, and total ocular symptom scores after 3D viewing had a significant correlation (p < 0.05), implying direct associations among these factors. Conclusions The decrease of accommodative ability after 3D viewing was validated by both subjective and objective methods in our study. Further, the deterioration of accommodative ability and ocular surface stability may be causative factors of visual asthenopia in individuals viewing 3D displays. PMID:24612686

PRESERVATIVES FROM THE EYE DROPS AND THE OCULAR SURFACE

PubMed Central

Coroi, Mihaela Cristina; Bungau, Simona; Tit, Mirela

2015-01-01

The use of preservatives in eye drops (eyewashes) has known glory at the beginning, but the side effects that they have on the ocular surface have led to a decrease of their popularity. Lachrymal film dysfunction, ocular hyperemia, dotted keratitis or toxic keratopathy were reported and analyzed in terms of pathophysiological mechanism of the role played by preservatives in ophthalmic drops (eyewashes). This article reviews the most common preservatives and the existing alternatives for the maintenance of the eye sterile drops. PMID:27373107

The Relationship Between High-Order Aberration and Anterior Ocular Biometry During Accommodation in Young Healthy Adults

PubMed Central

Ke, Bilian; Mao, Xinjie; Jiang, Hong; He, Jichang; Liu, Che; Li, Min; Yuan, Ying

2017-01-01

Purpose This study investigated the anterior ocular anatomic origin of high-order aberration (HOA) components using optical coherence tomography and a Shack-Hartmann wavefront sensor. Methods A customized system was built to simultaneously capture images of ocular wavefront aberrations and anterior ocular biometry. Relaxed, 2-diopter (D) and 4-D accommodative states were repeatedly measured in 30 young subjects. Custom software was used to correct optical distortions and measure biometric parameters from the images. Results The anterior ocular biometry changed during 2-D accommodation, in which central lens thickness, ciliary muscle thicknesses at 1 mm posterior to the scleral spur (CMT1), and the maximum value of ciliary muscle thickness increased significantly, whereas anterior chamber depth, CMT3, radius of anterior lens surface curvature (RAL), and radius of posterior lens surface curvature (RPL) decreased significantly. The changes in the anterior ocular parameters during 4-D accommodation were similar to those for the 2-D accommodation. \\begin{document}\

Three-dimensional confocal microscopy of the living cornea and ocular lens

NASA Astrophysics Data System (ADS)

Masters, Barry R.

1991-07-01

The three-dimensional reconstruction of the optic zone of the cornea and the ocular crystalline lens has been accomplished using confocal microscopy and volume rendering computer techniques. A laser scanning confocal microscope was used in the reflected light mode to obtain the two-dimensional images from the cornea and the ocular lens of a freshly enucleated rabbit eye. The light source was an argon ion laser with a 488 nm wavelength. The microscope objective was a Leitz X25, NA 0.6 water immersion lens. The 400 micron thick cornea was optically sectioned into 133 three micron sections. The semi-transparent cornea and the in-situ ocular lens was visualized as high resolution, high contrast two-dimensional images. The structures observed in the cornea include: superficial epithelial cells and their nuclei, basal epithelial cells and their 'beaded' cell borders, basal lamina, nerve plexus, nerve fibers, nuclei of stromal keratocytes, and endothelial cells. The structures observed in the in- situ ocular lens include: lens capsule, lens epithelial cells, and individual lens fibers. The three-dimensional data sets of the cornea and the ocular lens were reconstructed in the computer using volume rendering techniques. Stereo pairs were also created of the two- dimensional ocular images for visualization. The stack of two-dimensional images was reconstructed into a three-dimensional object using volume rendering techniques. This demonstration of the three-dimensional visualization of the intact, enucleated eye provides an important step toward quantitative three-dimensional morphometry of the eye. The important aspects of three-dimensional reconstruction are discussed.

Translational Immunoimaging and Neuroimaging Demonstrate Corneal Neuroimmune Crosstalk.

PubMed

Hamrah, Pedram; Seyed-Razavi, Yashar; Yamaguchi, Takefumi

2016-11-01

Corneal immunoimaging and neuroimaging approaches facilitate in vivo analyses of the cornea, including high-resolution imaging of corneal immune cells and nerves. This approach facilitates the analyses of underlying immune and nerve alterations not detected by clinical slit-lamp examination alone. In this review, we describe recent work performed in our translational ocular immunology center with a focus on "bench-to-bedside" and "bedside-to-bench" research. The ability to visualize dendritiform immune cells (DCs) in patients with laser in vivo confocal microscopy (IVCM), recently discovered in the central murine cornea, has allowed us to demonstrate their utility as a potential surrogate biomarker for inflammatory ocular surface diseases. This biomarker for inflammation allows the measurement of therapeutic efficacy of anti-inflammatory drugs and its utility as an endpoint in clinical trials with high interobserver agreement. IVCM image analyses from our studies has demonstrated a significant increase in DC density and size in ocular disease, a positive correlation between DC density and clinical signs and symptoms of disease and pro-inflammatory tear cytokines, and a strong negative correlation between DC density and subbasal nerve density. In conjunction with preclinical research investigating the inflammatory state in a partial or fully denervated cornea, our results indicated that corneal nerves are directly involved in the regulation of homeostasis and immune privilege in the cornea.

Dry eye disease and uveitis: A closer look at immune mechanisms in animal models of two ocular autoimmune diseases.

PubMed

Bose, Tanima; Diedrichs-Möhring, Maria; Wildner, Gerhild

2016-12-01

Understanding the immunopathogenesis of autoimmune and inflammatory diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a role in one subtype of disease, Sjögren' syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which adequately represents both diseases. However, there is evidence to suggest that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies. Copyright © 2016 Elsevier B.V. All rights reserved.

Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride

PubMed Central

Liang, H; Baudouin, C; Pauly, A; Brignole-Baudouin, F

2008-01-01

Aim: To compare the conjunctival and corneal reactions of commercially available solution of latanoprost (Xalatan) and preservative-free (PF) tafluprost in rabbits. Methods: The rabbits received 50 μl of phosphate-buffered saline (PBS), PF-tafluprost 0.0015%, latanoprost 0.005% or benzalkonium chloride (BAK) 0.02%; all solutions were applied at 5 min intervals for a total of 15 times. The ocular surface toxicity was investigated using slit-lamp biomicroscopy examination, flow cytometry (FCM) and on imprints for CD45 and tumour necrosis factor-receptor 1 (TNFR1) conjunctival impression cytology (CIC) and corneal in vivo confocal microscopy (IVCM). Standard immunohistology also assessed inflammatory/apoptotic cells. Results: Clinical observation and IVCM images showed the highest ocular surface toxicity with latanoprost and BAK, while PF-tafluprost and PBS eyes presented almost normal corneoconjunctival aspects. FCM showed a higher expression of CD45+ and TNFR1+ in latanoprost- or BAK-instilled groups, compared with PF-tafluprost and PBS groups. Latanoprost induced fewer positive cells for inflammatory marker expressions in CIC specimens compared with BAK-alone, both of which were higher than with PF-tafluprost or PBS. Immunohistology showed the same tendency of toxic ranking. Conclusion: The authors confirm that rabbit corneoconjunctival surfaces presented a better tolerance when treated with PF-tafluprost compared with commercially available latanoprost or BAK solution. PMID:18723745

Evaluation of conjunctival inflammatory status by confocal scanning laser microscopy and conjunctival brush cytology in patients with atopic keratoconjunctivitis (AKC)

PubMed Central

Wakamatsu, Tais Hitomi; Okada, Naoko; Kojima, Takashi; Matsumoto, Yukihiro; Ibrahim, Osama M.A.; Adan, Enrique Sato; Fukagawa, Kazumi; Katakami, Chikako; Tsubota, Kazuo; Shimazaki, Jun; Fujishima, Hiroshi

2009-01-01

Purpose To elucidate the status of the conjunctival inflammation in atopic keratoconjunctivitis (AKC) using laser scanning confocal microscopy and compare the relevant findings with conjunctival brush cytology in a prospective controlled study. Methods Twenty eyes from 20 AKC patients as well as 16 eyes from 16 age and sex matched normal subjects were studied. The subjects underwent tear film break-up time (BUT), fluorescein and Rose Bengal staining of the ocular surface, conjunctival confocal microscopy, Schirmer test, and brush cytology. Brush cytology specimens and in vivo confocal microscopy scans underwent evaluation for inflammatory cell densities. Results Brush cytology specimens and in vivo confocal microscopy scans from AKC patients revealed significantly higher numbers of inflammatory cells (p<0.05). Conjunctival inflammatory cell density showed a negative correlation with tear stability and a positive correlation with vital staining scores and conjunctival injection grades. The extent of conjunctival inflammation assessed by in vivo confocal microscopy showed a strong positive linear correlation with the inflammation status evaluated by brush cytology. The corneal inflammatory cell density assessed by in vivo confocal microscopy showed a significant negative correlation with tear stability and a positive linear correlation with corneal fluorescein staining. Conclusions Confocal scanning laser microscopy is an efficient, noninvasive, and a promising tool for the quantitative assessment of conjunctival inflammation, a parameter of this new technology which correlated well with subjective and objective ocular surface clinical findings. PMID:19693288

Altered gene expression in conjunctival squamous cell carcinoma.

PubMed

Mahale, Alka; Alkatan, Hind; Alwadani, Saeed; Othman, Maha; Suarez, Maria J; Price, Antoinette; Al-Hussain, Hailah; Jastaneiah, Sabah; Yu, Wayne; Maktabi, Azza; Deepak, Edward P; Eberhart, Charles G; Asnaghi, Laura

2016-05-01

Conjunctival squamous cell carcinoma is a malignancy of the ocular surface. The molecular drivers responsible for the development and progression of this disease are not well understood. We therefore compared the transcriptional profiles of eight snap-frozen conjunctival squamous cell carcinomas and one in situ lesion with normal conjunctival specimens in order to identify diagnostic markers or therapeutic targets. RNA was analyzed using oligonucleotide microarrays, and a wide range of transcripts with altered expression identified, including many dysregulated in carcinomas arising at other sites. Among the upregulated genes, we observed more than 30-fold induction of the matrix metalloproteinases, MMP-9 and MMP-11, as well as a prominent increase in the mRNA level of a calcium-binding protein important for the intracellular calcium signaling, S100A2, which was induced over 20-fold in the tumor cohort. Clusterin was the most downregulated gene, with an approximately 180-fold reduction in the mRNA expression. These alterations were all confirmed by qPCR in the samples used for initial microarray analysis. In addition, immunohistochemical analysis confirmed the overexpression of MMP-11 and S100A2, as well as reductions in clusterin, in several independent in situ carcinomas of conjunctiva. These data identify a number of alterations, including upregulation of MMP-9, MMP-11, and S100A2, as well as downregulation of clusterin, associated with epithelial tumorigenesis in the ocular surface.

Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to ocular tissues including retina and cornea.

PubMed

Johnson, Leslie N; Cashman, Siobhan M; Kumar-Singh, Rajendra

2008-01-01

As in other organ systems, gene and drug delivery to ocular tissues such as the retina and cornea is hampered by inefficient penetration of therapeutic molecules across the plasma membrane. We describe the use of a novel peptide for ocular delivery (POD) with protein transduction properties, for delivery of small and large molecules across the plasma membrane. POD enters cells within 5 minutes in a temperature dependent manner. POD can compact and deliver plasmid DNA, achieving transgene expression in >50% of human embryonic retinoblasts. Delivery of small interfering RNA (siRNA) duplexes to cells using POD, allowed for silencing of transgene expression by >50%. POD could also be used to deliver quantum dots in vitro and in vivo. Upon ocular delivery, POD rapidly entered neural retina and localized to retinal pigment epithelium (RPE), photoreceptor, and ganglion cells. Additionally, POD was able to enter corneal epithelium, sclera, choroid, and the dura of the optic nerve via topical application. POD also functions as a bacteriostatic, a useful property for a carrier of molecules to post mitotic neural ocular tissues.

Improvements in Signs and Symptoms of Dry Eye after Instillation of 2% Rebamipide.

PubMed

Igarashi, Tsutomu; Fujita, Miho; Yamada, Yumi; Kobayashi, Maika; Fujimoto, Chiaki; Takahashi, Hisatomo; Igarashi, Toru; Nakano, Yuichiro; Suzuki, Hisaharu; Takahashi, Hiroshi

2015-01-01

Because dry eye greatly reduces quality of life, this study aimed to examine rebamipide instillation in patients with dry eye and assess the improvement of signs and symptoms as evaluated with the Ocular Surface Disease Index, which is the most popular index and is highly reliable. From June 2013 through January 2014, we examined 50 eyes of 25 patients with dry eye (6 men and 19 woman) at our institution. Dry eye was diagnosed on the basis of the presence of symptoms, tear dynamics, and ocular surface abnormalities according to the Japanese criteria for dry eye. Before being enrolled, all patients underwent ocular surface health assessment, including history interviews, and completed the Ocular Surface Disease Index questionnaire. Patients received 2% rebamipide ophthalmic solution 4 times daily for 4 weeks. Signs and symptoms were analyzed before and 4 weeks after rebamipide administration. Tear dynamics, tear break-up time, and ocular surface abnormalities were measured and compared between before and 4 weeks after rebamipide administration. Of the 25 patients, 9 had definite dry eye and 16 had probable dry eye. Tear break-up time and the fluorescein staining score significantly improved after 4 weeks. However, no significant change was observed for the Schirmer test I and the lissamine green staining score. The administration of 2% rebamipide 4 times daily for 4 weeks improves the signs and symptoms of dry eye and improves patients' quality of life.

Plasma Rich in Growth Factors for the Treatment of Ocular Surface Diseases.

PubMed

Anitua, Eduardo; Muruzabal, Francisco; de la Fuente, María; Merayo, Jesús; Durán, Juan; Orive, Gorka

2016-07-01

The purpose of this work is to describe and review the technology of plasma rich in growth factors (PRGF), a novel blood derivative product, in the treatment of ocular surface disorders. To demonstrate the importance of this technology in the treatment of ocular pathologies, a thorough review of the preclinical and clinical literature results obtained following use of the different therapeutic formulations of PRGF was carried out. A literature search for applications of PGRF plasma in the ophthalmology field was carried out using the PubMed database. PRGF involves the use of patient's own biologically active proteins, growth factors, and biomaterial scaffolds for therapeutic purposes. This procedural technology is gaining interest in regenerative medicine due to its potential to stimulate and accelerate the tissue healing processes. The versatility and biocompatibility of this technology opens the door to a personalized medicine on ocular tissue regeneration. This review discusses the state of the art of the new treatments and technologies developed to promote ocular surface tissue regeneration. The standardized protocol that has been developed to source eye drops from PRGF technology is also described. The preclinical research, together with the most relevant clinical applications are summarized and discussed. The preliminary results suggest that the use of PRGF to enhance ocular tissue regeneration is safe and efficient.

Impact of wildfire smoke in Buenos Aires, Argentina, on ocular surface.

PubMed

Berra, Martin; Galperín, Gustavo; Dawidowski, Laura; Tau, Julia; Márquez, Isabel; Berra, Alejandro

2015-01-01

To evaluate the acute impact of the wildfire smoke episode in 2008 on the ocular surface of subjects living in the Metropolitan Area of Buenos Aires (MABA). A total of 86 subjects were evaluated: Group 1 comprised patients from a public ophthalmology hospital (N=35) and Group 2 comprised healthy volunteers (N=51). All subjects answered a questionnaire on ocular symptoms and underwent ophthalmologic examination [bulbar conjunctival hyperemia, corneal fluorescein staining, rose bengal vital staining, tear break-up time (TBUT), Schirmer I test, tear lysozyme, and impression cytology] during and after the acute episode. Concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), and particulate matter (PM) were measured before, during, and after the acute episode. Both groups showed a statically significant increase in ocular symptoms and bulbar conjunctival hyperemia and a statically significant decrease in tear break-up time during the acute episode. Group 1 showed more severe symptoms and a statistically significant increase in fluorescein and rose bengal staining intensities during the acute episode. We found a significant negative correlation between ocular symptoms and tear break-up time. During the episode, the levels of CO, NO2, and particulate matter in MABA were four times higher than the usual average levels for the same period in 2007 and 2009. Increased air pollution from the burning of biomass is associated with a decrease in the stability of the tear film (TBUT), generating areas of ocular surface exposure that may be the cause of the increased feeling of irritation. Group 1 was more affected by not having a healthy ocular surface, and thus consulted an ophthalmologist. Cytological changes in the conjunctiva were not observed, which could be due to the short duration of the episode.

Restoring conjunctival tolerance by topical nuclear factor-κB inhibitors reduces preservative-facilitated allergic conjunctivitis in mice.

PubMed

Guzmán, Mauricio; Sabbione, Florencia; Gabelloni, María Laura; Vanzulli, Silvia; Trevani, Analía Silvina; Giordano, Mirta Nilda; Galletti, Jeremías Gastón

2014-09-04

To evaluate the role of nuclear factor-κB (NF-κB) activation in eye drop preservative toxicity and the effect of topical NF-κB inhibitors on preservative-facilitated allergic conjunctivitis. Balb/c mice were instilled ovalbumin (OVA) combined with benzalkonium chloride (BAK) and/or NF-κB inhibitors in both eyes. After immunization, T-cell responses and antigen-induced ocular inflammation were evaluated. Nuclear factor-κB activation and associated inflammatory changes also were assessed in murine eyes and in an epithelial cell line after BAK exposure. Benzalkonium chloride promoted allergic inflammation and leukocyte infiltration of the conjunctiva. Topical NF-κB inhibitors blocked the disruptive effect of BAK on conjunctival immunological tolerance and ameliorated subsequent ocular allergic reactions. In line with these findings, BAK induced NF-κB activation and the secretion of IL-6 and granulocyte-monocyte colony-stimulating factor in an epithelial cell line and in the conjunctiva of instilled mice. In addition, BAK favored major histocompatibility complex (MHC) II expression in cultured epithelial cells in an NF-κB-dependent fashion after interaction with T cells. Benzalkonium chloride triggers conjunctival epithelial NF-κB activation, which seems to mediate some of its immune side effects, such as proinflammatory cytokine release and increased MHC II expression. Breakdown of conjunctival tolerance by BAK favors allergic inflammation, and this effect can be prevented in mice by topical NF-κB inhibitors. These results suggest a new pharmacological target for preservative toxicity and highlight the importance of conjunctival tolerance in ocular surface homeostasis. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Antiadhesive Character of Mucin O-glycans at the Apical Surface of Corneal Epithelial Cells

PubMed Central

Sumiyoshi, Mika; Ricciuto, Jessica; Tisdale, Ann; Gipson, Ilene K.; Mantelli, Flavio; Argüeso, Pablo

2008-01-01

Purpose Prolonged contact of opposite mucosal surfaces, which occurs on the ocular surface, oral cavity, reproductive tract, and gut, requires a specialized apical cell surface that prevents adhesion. The purpose of this study was to evaluate the contribution of mucin O-glycans to the antiadhesive character of human corneal–limbal epithelial (HCLE) cells. Methods Mucin O-glycan biosynthesis in HCLE cells was disrupted by metabolic interference with benzyl-α-GalNAc. The cell surface mucin MUC16 and its carbohydrate epitope H185 were detected by immunofluorescence and Western blot. HCLE cell surface features were assessed by field emission scanning electron microscopy. Cell–cell adhesion assays were performed under static conditions and in a parallel plate laminar flow chamber. Results Benzyl-α-GalNAc disrupted the biosynthesis of O-glycans without affecting apomucin biosynthesis or cell surface morphology. Static adhesion assays showed that the apical surface of differentiated HCLE cells expressing MUC16 and H185 was more antiadhesive than undifferentiated HCLE cells, which lacked MUC16. Abrogation of mucin O-glycosylation in differentiated cultures with benzyl-α-GalNAc resulted in increased adhesion of applied corneal epithelial cells and corneal fibroblasts. The antiadhesive effect of mucin O-glycans was further demonstrated by fluorescence video microscopy in dynamic flow adhesion assays. Cationized ferritin labeling of the cell surface indicated that anionic repulsion did not contribute to the antiadhesive character of the apical surface. Conclusions These results indicate that epithelial O-glycans contribute to the antiadhesive properties of cell surface–associated mucins in corneal epithelial cells and suggest that alterations in mucin O-glycosylation are involved in the pathology of drying mucosal diseases (e.g., dry eye). PMID:18172093

Ocular Phenotype of Fbn2-Null Mice

PubMed Central

Shi, Yanrong; Tu, Yidong; Mecham, Robert P.; Bassnett, Steven

2013-01-01

Purpose. Fibrillin-2 (Fbn2) is the dominant fibrillin isoform expressed during development of the mouse eye. To test its role in morphogenesis, we examined the ocular phenotype of Fbn2−/− mice. Methods. Ocular morphology was assessed by confocal microscopy using antibodies against microfibril components. Results. Fbn2−/− mice had a high incidence of anterior segment dysgenesis. The iris was the most commonly affected tissue. Complete iridal coloboma was present in 37% of eyes. Dyscoria, corectopia and pseudopolycoria were also common (43% combined incidence). In wild-type (WT) mice, fibrillin-2-rich microfibrils are prominent in the pupillary membrane (PM) during development. In Fbn2-null mice, the absence of Fbn2 was partially compensated for by increased expression of fibrillin-1, although the resulting PM microfibrils were disorganized, compared with WTs. In colobomatous adult Fbn2−/− eyes, the PM failed to regress normally, especially beneath the notched region of the iris. Segments of the ciliary body were hypoplastic, and zonular fibers, although relatively plentiful, were unevenly distributed around the lens equator. In regions where the zonular fibers were particularly disturbed, the synchronous differentiation of the underlying lens fiber cells was affected. Conclusions. Fbn2 has an indispensable role in ocular morphogenesis in mice. The high incidence of iris coloboma in Fbn2-null animals implies a previously unsuspected role in optic fissure closure. The observation that fiber cell differentiation was disturbed in Fbn2−/− mice raises the possibility that the attachment of zonular fibers to the lens surface may help specify the equatorial margin of the lens epithelium. PMID:24130178

Clinical characterisation and cytological study of dry eye in patients with autoimmune disease.

PubMed

Guannan, Huang; Long, Su; Xia, Hua; Dong, Wang; Shaozhen, Zhao

2018-03-01

To assess the clinical characteristics and changes in ocular surface cytology of dry eye in patients with systemic autoimmune disease. The case-control study was conducted in the Second Hospital of Tianjin Medical University, Tianjin, China, from February 2016 to January 2017, and comprised systemic autoimmune disease patients and healthy controls. Schirmer's I test, tear breakup time test, and fluorescein staining were performed on all subjects. Both groups were evaluated for dry eye with the current diagnostic criteria. Conjunctival impression cytology and the morphology of epithelial cells were observed in both groups of subjects. Flow cytometry was used to identify the amount of apoptosis. SPSS 15 was used to analyse the data. Each of the two groups had 60(50%) subjects each. The morbidity of dry eye in the control group was 17(28.3%), while it was 31(51.7%) in the patients (p<0.01). Among the patients with dry eye, the severity level of cells obtained by conjunctival impression sampling was significantly higher in patients than in controls (p<0.01). The percentage of conjunctival epithelial cells undergoing apoptosis was higher in patients with dry eye than in patients without dry eye in each group, and among patients with dry eye, the percentage of conjunctival epithelial cells undergoing apoptosis was higher in the patients than in controls (p<0.01 each). The cell injury on the ocular surface was more serious in subjects with dry eye in systemic autoimmune disease than in subjects with dry eye in healthy controls.

Design considerations of a real-time clinical confocal microscope

NASA Astrophysics Data System (ADS)

Masters, Barry R.

1991-06-01

A real-time clinical confocal light microscope provides the ophthalmologist with a new tool for the observation of the cornea and the ocular lens. In addition, the ciliary body, the iris, and the sclera can be observed. The real-time light microscopic images have high contrast and resolution. The transverse resolution is about one half micron and the range resolution is one micron. The following observations were made with visible light: corneal epithelial cells, wing cells, basal cells, Bowman's membrane, nerve fibers, basal lamina, fibroblast nuclei, Descemet's membrane, endothelial cells. Observation of the in situ ocular lens showed lens capsule, lens epithelium, lens fibrils, the interior of lens fibrils. The applications of the confocal microscope include: eye banking, laser refractive surgery, observation of wound healing, observation of the iris, the sciera, the ciliary body, the ocular lens, and the intraocular lens. Digital image processing can produce three-dimensional reconstructions of the cornea and the ocular lens.

Influence of Light Emitting Diode-Derived Blue Light Overexposure on Mouse Ocular Surface.

PubMed

Lee, Hyo Seok; Cui, Lian; Li, Ying; Choi, Ji Suk; Choi, Joo-Hee; Li, Zhengri; Kim, Ga Eon; Choi, Won; Yoon, Kyung Chul

2016-01-01

To investigate the influence of overexposure to light emitting diode (LED)-derived light with various wavelengths on mouse ocular surface. LEDs with various wavelengths were used to irradiate C57BL/6 mice at an energy dose of 50 J/cm2, twice a day, for 10 consecutive days. The red, green, and blue groups represented wavelengths of 630 nm, 525 nm, and 410 nm, respectively. The untouched group (UT) was not exposed to LED light and served as the untreated control. Tear volume, tear film break-up time (TBUT), and corneal fluorescein staining scores were measured on days 1, 3, 5, 7, and 10. Levels of interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were measured in the cornea and conjunctiva using a multiplex immunobead assay at day 10. Levels of malondialdehyde (MDA) were measured with an enzyme-linked immunosorbent assay. Flow cytometry, 2'7'-dichlorofluorescein diacetate (DCF-DA) assay, histologic analysis, immunohistochemistry with 4-hydroxynonenal, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining were also performed. TBUT of the blue group showed significant decreases at days 7 and 10, compared with the UT and red groups. Corneal fluorescein staining scores significantly increased in the blue group when compared with UT, red, and green groups at days 5, 7, and 10. A significant increase in the corneal levels of IL-1β and IL-6 was observed in the blue group, compared with the other groups. The blue group showed significantly increased reactive oxygen species production in the DCF-DA assay and increased inflammatory T cells in the flow cytometry. A significantly increased TUNEL positive cells was identified in the blue group. Overexposure to blue light with short wavelengths can induce oxidative damage and apoptosis to the cornea, which may manifest as increased ocular surface inflammation and resultant dry eye.

Association between clinical diagnostic tests and health-related quality of life surveys in patients with dry eye syndrome.

PubMed

Mizuno, Yoshinobu; Yamada, Masakazu; Miyake, Yozo

2010-07-01

This study was performed to assess the impact of dry eye on patients' quality of life (QOL) and to analyze the association between subjective symptoms and ocular surface findings of dry eye. The study population consisted of 158 patients with dry eye aged 20 years or older who visited any of the 15 medical care facilities enrolled in the study. The backgrounds and ocular findings of the patients were investigated, and their QOL was evaluated with the Japanese version of the 25-item National Eye Institute Visual Functioning Questionnaire (VFQ-25) and of the Medical Outcomes Study (MOS) 8-item Short-Form Health Survey (SF-8) to examine the association between subjective symptoms and ocular surface findings. Of the patients enrolled, 15 were men and 143 were women, and their average age was 62.5 +/- 12.6 years. Sixty patients (38.0%) had comorbid Sjögren syndrome (SS). The results of Schirmer testing, fluorescein staining, and rose bengal staining for SS patients were significantly worse than those for the non-SS patients, but the VFQ-25 and SF-8 scores were not significantly different between the SS and non-SS patients. In the ocular surface findings, a weak association between the fluorescein staining scores and general vision scores, a subscale of the VFQ-25, was found. However, the ocular surface findings and VFQ-25/SF-8 results in the simple correlation analysis as well as in the multiple linear regression analysis showed no significant associations. Ocular surface findings and QOL scores of patients with dry eye appear to disagree. Therefore, it is necessary to address subjective symptoms and QOL scores in addition to examination findings when evaluating dry eye.

Expression of prostaglandin E receptor subtype EP4 in conjunctival epithelium of patients with ocular surface disorders: case-control study.

PubMed

Ueta, Mayumi; Sotozono, Chie; Yamada, Keiko; Yokoi, Norihiko; Inatomi, Tsutomu; Kinoshita, Shigeru

2012-01-01

To confirm the downregulation of PTGER4 mRNA in the conjunctiva of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and ocular cicatricial pemphigoid (OCP) patients and to examine the expression of its EP4 protein in the conjunctival epithelium of patients with various ocular surface disorders. Case-control study. We performed quantitative reverse transcription-PCR (RT-PCR) analysis of PTGER4 mRNA in conjunctival tissue sections from patients with SJS/TEN and OCP to confirm the downregulation of PTGER4 mRNA expression. We also analysed EP4 immunohistologically in other ocular surface disorders. Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to chemical eye burns, subacute SJS/TEN or chronic SJS/TEN, chronic OCP, severe graft versus host disease (GVHD) and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The expression of PTGER4 mRNA and EP4 protein assessed by quantitative RT-PCR assay and immunohistological methods. PTGER4 mRNA was significantly lower in conjunctival tissues from SJS and OCP patients than in the control conjunctivochalasis samples. EP4 protein was detected in conjunctival epithelium from patients with chemical eye burn and in control conjunctival epithelium from patients with conjunctivochalasis. Its expression varied in conjunctival epithelium from patients with Mooren's ulcer. We did not detect EP4 immunoreactivity in conjunctival epithelium from patients with subacute SJS/TEN, severe GVHD, chronic SJS/TEN or OCP. The strong downregulation of EP4 expression in conjunctival epithelium from patients with OCP or SJS/TEN may be attributable to ocular surface inflammation.

Expression of prostaglandin E receptor subtype EP4 in conjunctival epithelium of patients with ocular surface disorders: case-control study

PubMed Central

Ueta, Mayumi; Sotozono, Chie; Yamada, Keiko; Yokoi, Norihiko; Inatomi, Tsutomu; Kinoshita, Shigeru

2012-01-01

Objectives To confirm the downregulation of PTGER4 mRNA in the conjunctiva of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and ocular cicatricial pemphigoid (OCP) patients and to examine the expression of its EP4 protein in the conjunctival epithelium of patients with various ocular surface disorders. Design Case-control study. Setting and participants We performed quantitative reverse transcription-PCR (RT-PCR) analysis of PTGER4 mRNA in conjunctival tissue sections from patients with SJS/TEN and OCP to confirm the downregulation of PTGER4 mRNA expression. We also analysed EP4 immunohistologically in other ocular surface disorders. Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to chemical eye burns, subacute SJS/TEN or chronic SJS/TEN, chronic OCP, severe graft versus host disease (GVHD) and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. Primary and secondary outcome measures The expression of PTGER4 mRNA and EP4 protein assessed by quantitative RT-PCR assay and immunohistological methods. Results PTGER4 mRNA was significantly lower in conjunctival tissues from SJS and OCP patients than in the control conjunctivochalasis samples. EP4 protein was detected in conjunctival epithelium from patients with chemical eye burn and in control conjunctival epithelium from patients with conjunctivochalasis. Its expression varied in conjunctival epithelium from patients with Mooren's ulcer. We did not detect EP4 immunoreactivity in conjunctival epithelium from patients with subacute SJS/TEN, severe GVHD, chronic SJS/TEN or OCP. Conclusions The strong downregulation of EP4 expression in conjunctival epithelium from patients with OCP or SJS/TEN may be attributable to ocular surface inflammation. PMID:23065448

Effect of Stratification on Surface Properties of Corneal Epithelial Cells

PubMed Central

Yáñez-Soto, Bernardo; Leonard, Brian C.; Raghunathan, Vijay Krishna; Abbott, Nicholas L.; Murphy, Christopher J.

2015-01-01

Purpose The purpose of this study was to determine the influence of mucin expression in an immortalized human corneal epithelial cell line (hTCEpi) on the surface properties of cells, such as wettability, contact angle, and surface heterogeneity. Methods hTCEpi cells were cultured to confluence in serum-free medium. The medium was then replaced by stratification medium to induce mucin biosynthesis. The mucin expression profile was analyzed using quantitative PCR and Western blotting. Contact angles were measured using a two-immiscible liquid method, and contact angle hysteresis was evaluated by tilting the apparatus and recording advancing and receding contact angles. The spatial distribution of mucins was evaluated with fluorescently labeled lectin. Results hTCEpi cells expressed the three main ocular mucins (MUC1, MUC4, and MUC16) with a maximum between days 1 and 3 of the stratification process. Upon stratification, cells caused a very significant increase in contact angle hysteresis, suggesting the development of spatially discrete and heterogeneously distributed surface features, defined by topography and/or chemical functionality. Although atomic force microscopy measurements showed no formation of appreciable topographic features on the surface of the cells, we observed a significant increase in surface chemical heterogeneity. Conclusions The surface chemical heterogeneity of the corneal epithelium may influence the dynamic behavior of tear film by “pinning” the contact line between the cellular surface and aqueous tear film. Engineering the surface properties of corneal epithelium could potentially lead to novel treatments in dry eye disease. PMID:26747762

UV-blocking spectacle lens protects against UV-induced decline of visual performance.

PubMed

Liou, Jyh-Cheng; Teng, Mei-Ching; Tsai, Yun-Shan; Lin, En-Chieh; Chen, Bo-Yie

2015-01-01

Excessive exposure to sunlight may be a risk factor for ocular diseases and reduced visual performance. This study was designed to examine the ability of an ultraviolet (UV)-blocking spectacle lens to prevent visual acuity decline and ocular surface disorders in a mouse model of UVB-induced photokeratitis. Mice were divided into 4 groups (10 mice per group): (1) a blank control group (no exposure to UV radiation), (2) a UVB/no lens group (mice exposed to UVB rays, but without lens protection), (3) a UVB/UV400 group (mice exposed to UVB rays and protected using the CR-39™ spectacle lens [UV400 coating]), and (4) a UVB/photochromic group (mice exposed to UVB rays and protected using the CR-39™ spectacle lens [photochromic coating]). We investigated UVB-induced changes in visual acuity and in corneal smoothness, opacity, and lissamine green staining. We also evaluated the correlation between visual acuity decline and changes to the corneal surface parameters. Tissue sections were prepared and stained immunohistochemically to evaluate the structural integrity of the cornea and conjunctiva. In blank controls, the cornea remained undamaged, whereas in UVB-exposed mice, the corneal surface was disrupted; this disruption significantly correlated with a concomitant decline in visual acuity. Both the UVB/UV400 and UVB/photochromic groups had sharper visual acuity and a healthier corneal surface than the UVB/no lens group. Eyes in both protected groups also showed better corneal and conjunctival structural integrity than unprotected eyes. Furthermore, there were fewer apoptotic cells and less polymorphonuclear leukocyte infiltration in corneas protected by the spectacle lenses. The model established herein reliably determines the protective effect of UV-blocking ophthalmic biomaterials, because the in vivo protection against UV-induced ocular damage and visual acuity decline was easily defined.

Ocular Nerve Growth Factor (NGF) and NGF Eye Drop Application as Paradigms to Investigate NGF Neuroprotective and Reparative Actions.

PubMed

Tirassa, Paola; Rosso, Pamela; Iannitelli, Angela

2018-01-01

The eye is a central nervous system structure that is uniquely accessible to local treatment. Through the ocular surface, it is possible to access the retina, optic nerve, and brain. Animal models of retina degeneration or optic nerve crush could thus serve as tools to investigate whether and how factors, which are anterogradely or retrogradely transported through the optic nerve, might contribute to activate neuroprotection and eventually regeneration. Among these factors, nerve growth factor (NGF) plays a crucial role during development of the visual system, as well as during the entire life span, and in pathological conditions. The ability of NGF to exert survival and trophic actions on the retina and brain cells when applied intraocularly and topically as eye drops is critically reviewed here, together with the effects of ocular neurotrophins on neuronal pathways influencing body rhythm, cognitions, and behavioral functions. The latest data from animal models and humans are presented, and the mechanism of action of ocularly administered NGF is discussed. NGF eye drops are proposed as an experimental strategy to investigate the role and cellular targets of neurotrophins in the mechanism(s) underlying neurodegeneration/regeneration and their involvement in the regulation of neurological and behavioral dysfunctions.

Scleral patch grafts in the management of uveal and ocular surface tumors.

PubMed

Barman, Manabjyoti; Finger, Paul T; Milman, Tatyana

2012-12-01

To evaluate the outcome of scleral patch grafts in a series of patients undergoing management for uveal and ocular surface tumors. Case series. Ten patients underwent scleral patch grafting. Five patients had uveal melanoma with extrascleral extension, 2 patients had scleromalacia secondary to plaque radiotherapy for uveal melanoma, 2 patients had suspicious uveoscleral nevi, and 1 patient had invasive conjunctival squamous cell carcinoma with scleral necrosis. Retrospective, interventional, noncomparative chart review of patients undergoing treatment for ocular tumors followed by scleral grafts in a tertiary eye care center in the United States between September 2003 and January 2011. Sclera was reconstructed with allogenic scleral grafts. Clinical observations were performed after grafting. Structural integrity, appearance, and stability of the grafts. Ten patients were reviewed. All melanoma cases received plaque radiotherapy with palladium 103. The cases with nevi and squamous cell carcinoma underwent local resection with cryotherapy as primary treatment. In 8 cases, scleral grafting was performed as part of the initial surgery. In all of these cases, satisfactory anatomic and functional outcomes were achieved. In 2 cases with scleromalacia secondary to radiotherapy for uveal melanoma, grafts were placed several years after the initial treatment. In these 2 cases, one showed signs of graft retraction, whereas another showed graft thinning. No patients experienced graft infection, rejection, or tumor recurrence. In this series, scleral grafts were well accepted when placed as part of the primary tumor management despite synchronous radiotherapy, scleral resection, or cryotherapy. Grafting was less successful when performed as a late procedure for radiation-induced scleromalacia. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Ocular Manifestations of Acquired Immunodeficiency Syndrome.

PubMed

Kim, Young Shin; Sun, Hae Jung; Kim, Tae Hyong; Kang, Kui Dong; Lee, Sung Jin

2015-08-01

To investigate the patterns and risk factors of the ocular manifestations of acquired immunodeficiency syndrome (AIDS) and their correlation with CD4+ count in the era of highly active antiretroviral therapy (HAART). This retrospective study examined 127 AIDS patients who presented to Soonchunhyang University Hospital. Data were collected from patient interviews, clinical examinations, and laboratory investigations. Ophthalmologic examinations included the best-corrected visual acuity, intraocular pressure, anterior segment and adnexal examination, and dilated fundus examination. Of the 127 patients with AIDS, 118 were on HAART and 9 were not. The mean CD4+ count was 266.7 ± 209.1 cells/µL. There were ocular manifestations in 61 patients (48.0%). The incidence of anterior segment manifestations was higher than posterior segment manifestations at 28.3% and 19.7%, respectively. The mean CD4+ count was significantly (p < 0.05) lower in the patients with posterior versus anterior segment ocular manifestations. The most common ocular manifestation was retinal microvasculopathy (15.0%), followed by keratoconjunctivitis sicca (14.2%), conjunctival microvasculopathy (9.4%), cytomegalovirus retinitis (3.1%), herpes zoster ophthalmicus (2.4%), and blepharitis (1.6%). Retinal microvasculopathy and cytomegalovirus retinitis were common in patients with CD4+ counts <200 cells/µL, while keratoconjunctivitis sicca and conjunctival microvasculopathy were common in patients with CD4+ counts of 200 to 499 cells/µL. There was a significant (p < 0.05) association between ocular manifestation and CD4+ count or age. The introduction of HAART has changed the landscape of ocular presentations in patients with AIDS. In this study, anterior segment and external ocular manifestations occurred more frequently than posterior segment manifestations. Also, the mean CD4+ count was significantly lower in patients with posterior segment ocular manifestations versus anterior segment ocular manifestations. We found that CD4+ count and age >35 years were independent risk factors for developing ocular manifestations.

Ocular Manifestations of Acquired Immunodeficiency Syndrome

PubMed Central

Kim, Young Shin; Sun, Hae Jung; Kim, Tae Hyong; Kang, Kui Dong

2015-01-01

Purpose To investigate the patterns and risk factors of the ocular manifestations of acquired immunodeficiency syndrome (AIDS) and their correlation with CD4+ count in the era of highly active antiretroviral therapy (HAART). Methods This retrospective study examined 127 AIDS patients who presented to Soonchunhyang University Hospital. Data were collected from patient interviews, clinical examinations, and laboratory investigations. Ophthalmologic examinations included the best-corrected visual acuity, intraocular pressure, anterior segment and adnexal examination, and dilated fundus examination. Results Of the 127 patients with AIDS, 118 were on HAART and 9 were not. The mean CD4+ count was 266.7 ± 209.1 cells/µL. There were ocular manifestations in 61 patients (48.0%). The incidence of anterior segment manifestations was higher than posterior segment manifestations at 28.3% and 19.7%, respectively. The mean CD4+ count was significantly (p < 0.05) lower in the patients with posterior versus anterior segment ocular manifestations. The most common ocular manifestation was retinal microvasculopathy (15.0%), followed by keratoconjunctivitis sicca (14.2%), conjunctival microvasculopathy (9.4%), cytomegalovirus retinitis (3.1%), herpes zoster ophthalmicus (2.4%), and blepharitis (1.6%). Retinal microvasculopathy and cytomegalovirus retinitis were common in patients with CD4+ counts <200 cells/µL, while keratoconjunctivitis sicca and conjunctival microvasculopathy were common in patients with CD4+ counts of 200 to 499 cells/µL. There was a significant (p < 0.05) association between ocular manifestation and CD4+ count or age. Conclusions The introduction of HAART has changed the landscape of ocular presentations in patients with AIDS. In this study, anterior segment and external ocular manifestations occurred more frequently than posterior segment manifestations. Also, the mean CD4+ count was significantly lower in patients with posterior segment ocular manifestations versus anterior segment ocular manifestations. We found that CD4+ count and age >35 years were independent risk factors for developing ocular manifestations. PMID:26240508

Efficacy and Safety of Carbomer-Based Lipid-Containing Artificial Tear Formulations in Patients With Dry Eye Syndrome.

PubMed

Chung, So-Hyang; Lim, Sung A; Tchach, Hungwon

2016-02-01

To evaluate the efficacy and safety profile of carbomer-based lipid-containing artificial tear formulations (CBLAT) in patients with dry eye syndrome. A multicenter parallel-group study was conducted in 412 patients with dry eye syndrome. Of these patients, 221 switched from using artificial tears to CBLAT (switching group) and 191 added CBLAT to their current treatment (add-on group). Ocular symptom scores, ocular staining grades, tear film breakup time (tBUT), Schirmer I test value, and Korean dry eye level (as defined by the Korean Corneal Disease Study Group guidelines) were evaluated at baseline and after 4 weeks of treatment. After 4 weeks of treatment, ocular surface staining grade, tBUT, Schirmer I value, ocular irritation symptom scores, and the positive rate of visual symptom improved significantly in both groups. Mean reductions in ocular surface staining grades (-0.8 ± 0.9) and ocular irritation symptom scores (-0.8 ± 0.8) in the add-on group were significantly higher than those (-0.5 ± 0.8 and -0.6 ± 0.8) in the switching group (P < 0.01 and P < 0.05). The positive rate of visual symptoms (44.2%) in the add-on group was significantly higher than that (26.4%) in the switching group (P < 0.01). The decrease of Korean dry eye level was 30.1% in the switching group and 51.6% in the add-on group. More patients in the add-on group had decreased dry eye levels than those in the switching group (P < 0.0001). CBLAT improves ocular surface staining grades, tBUT, Schirmer I values, and ocular symptoms in patients with dry eye syndrome.

Ocular allergy and dry eye syndrome.

PubMed

Bielory, Leonard

2004-10-01

Ocular allergy is a common clinical disorder that includes dry eye syndrome in its differential diagnosis. While ocular allergy treatments have continued to evolve since the early 1990s when the new prescription topical agents became available, there have been no major advances in the treatment of dry eye syndrome other than changes in the chemical structures of various artificial tear formulations. This review is timely and relevant due to the recent FDA approval of several new agents for the treatment of dry eye syndrome. The literature reviewed brings the practicing allergist/clinical immunologist up to date on the recent understanding that T-cell activation plays a key role in dry eye syndrome immunopathophysiology. In addition, the parallel novel treatment developments are discussed, including new formulations for tear substitutes, topical cyclosporine A and purinergic receptor (P2Y2) agonists. The recent developments bode well for patients who are referred for ocular allergy, including dry eye syndrome. A new formulation for a tear substitute that generates a 'soft gel' covering the ocular surface (in situ) is ideal for early forms of dry syndrome, while topical cyclosporine is the first new real prescription treatment for patients with moderate to severe forms of dry eye. Another potential agent to revolutionize the treatment of various disorders is based on the discovery of the purinergic receptor agonists. This is not only relevant for the production of mucin and the change in tear fluid content, but it may also have implications for other sinopulmonary disorders such as cystic fibrosis and chronic sinusitis.

Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation.

PubMed

Bianchi, E; Ripandelli, G; Feher, J; Plateroti, A M; Plateroti, R; Kovacs, I; Plateroti, P; Taurone, S; Artico, M

2015-01-01

The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings.

Association of Cell Surface Mucins with Galectin-3 Contributes to the Ocular Surface Epithelial Barrier*

PubMed Central

Argüeso, Pablo; Guzman-Aranguez, Ana; Mantelli, Flavio; Cao, Zhiyi; Ricciuto, Jessica; Panjwani, Noorjahan

2009-01-01

Maintenance of an intact mucosal barrier is critical to preventing damage to and infection of wet-surfaced epithelia. The mechanism of defense has been the subject of much investigation, and there is evidence now implicating O-glycosylated mucins on the epithelial cell surface. Here we investigate a new role for the carbohydrate-binding protein galectin-3 in stabilizing mucosal barriers through its interaction with mucins on the apical glycocalyx. Using the surface of the eye as a model system, we found that galectin-3 colocalized with two distinct membrane-associated mucins, MUC1 and MUC16, on the apical surface of epithelial cells and that both mucins bound to galectin-3 affinity columns in a galactose-dependent manner. Abrogation of the mucin-galectin interaction in four different mucosal epithelial cell types using competitive carbohydrate inhibitors of galectin binding, β-lactose and modified citrus pectin, resulted in decreased levels of galectin-3 on the cell surface with concomitant loss of barrier function, as indicated by increased permeability to rose bengal diagnostic dye. Similarly, down-regulation of mucin O-glycosylation using a stable tetracycline-inducible RNA interfering system to knockdown c1galt1 (T-synthase), a critical galactosyltransferase required for the synthesis of core 1 O-glycans, resulted in decreased cell surface O-glycosylation, reduced cell surface galectin-3, and increased epithelial permeability. Taken together, these results suggest that galectin-3 plays a key role in maintaining mucosal barrier function through carbohydrate-dependent interactions with cell surface mucins. PMID:19556244

Biomaterials and Tissue Engineering Strategies for Conjunctival Reconstruction and Dry Eye Treatment

PubMed Central

Lu, Qiaozhi; Al-Sheikh, Osama; Elisseeff, Jennifer H.; Grant, Michael P.

2015-01-01

The ocular surface is a component of the anterior segment of the eye and is covered by the tear film. Together, they protect the vital external components of the eye from the environment. Injuries, surgical trauma, and autoimmune diseases can damage this system, and in severe cases, tissue engineering strategies are necessary to ensure proper wound healing and recovery. Dry eye is another major concern and a complicated disease affecting the ocular surface. More effective and innovative therapies are required for better outcomes in treating dry eye. This review focuses on the regenerative medicine of the conjunctiva, which is an essential part of the ocular surface system. Features and advances of different types of biomolecular materials, and autologous and allogeneic tissue grafts are summarized and compared. Specifically, vitrigel, a collagen membrane and novel material for use on the ocular surface, offers significant advantages over other biomaterials. This review also discusses a breakthrough microfluidic technology, “organ-on-a-chip” and its potential application in investigating new therapies for dry eye. PMID:26692712

Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders.

PubMed

Nebbioso, Marcella; Del Regno, Paola; Gharbiya, Magda; Sacchetti, Marta; Plateroti, Rocco; Lambiase, Alessandro

2017-08-13

The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology.

Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders

PubMed Central

Del Regno, Paola; Sacchetti, Marta; Plateroti, Rocco

2017-01-01

The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology. PMID:28805710

Comparison of ultrastructure, tight junction-related protein expression and barrier function of human corneal epithelial cells cultivated on amniotic membrane with and without air-lifting.

PubMed

Ban, Yuriko; Cooper, Leanne J; Fullwood, Nigel J; Nakamura, Takahiro; Tsuzuki, Masakatsu; Koizumi, Noriko; Dota, Atsuyoshi; Mochida, Chikako; Kinoshita, Shigeru

2003-06-01

To evaluate the usefulness of the air-lifting technique for culturing corneal limbal epithelial cells on amniotic membrane (AM) for use in ocular surface reconstruction. A cultured sheet that has a good barrier function should be better for this purpose. In corneal epithelium, tight junctions (TJ) play a vital role in the barrier function. The TJ complex includes the integral transmembrane proteins occludin and the claudins, and some membrane-associated proteins such as ZO-1. In this paper, we investigated the barrier function and the expression of TJ related proteins. Corneal limbal epithelium obtained from donor corneas and cultivated on acellular AM was divided into two groups. These were the non-air-lifting (Non-AL) group, which was continuously submerged in medium, and the air-lifting (AL) group, which was submerged in medium for 3 weeks, then exposed to air by lowering the medium level. Morphology and the permeability to horseradish peroxidase (HRP) were determined by electron microscopy. Tight junction (TJ)-related protein and mRNA expression changes were assessed by immunoblotting and reverse transcription-polymerase chain reaction. The cultures of both groups formed 4-5-layer-thick, well-stratified epithelium. The AL cultures had tightly packed epithelial cells with all the HRP/diaminobenzidine (DAB) reaction product accumulated on the apical surface of the superficial cells. The Non-AL culture, by contrast, had more loosely packed epithelial cells with larger intercellular spaces. The HRP/DAB reaction product penetrated the intercellular space to a depth of 3-4 cell layers. Statistically, there was a significant difference in intercellular spaces and desmosome count in the superficial cells between the groups. With AL, TJ-related proteins localized at the apical portion of the lateral membrane. TJ-related protein and mRNA amounts were not changed by AL while claudin subtype expression became more consistent and closer to that of in vivo corneal epithelium. The AL technique reduces intercellular spaces in the superficial cells and promotes the formation of the barrier function. It is useful in culturing corneal epithelial cells for use in ocular surface reconstruction.

Amniotic membrane transplantation for ocular disease: a review of the first 233 cases from the UK user group

PubMed Central

Saw, Valerie P J; Minassian, Darwin; Dart, John K G; Ramsay, Andrew; Henderson, Hugo; Poniatowski, Stefan; Warwick, Ruth M; Cabral, Suzanne

2007-01-01

Background Amniotic membrane transplantation (AMT), as a new tool in the armamentarium of therapies available for ocular surface problems, became widely available in the UK in 1998. This study evaluates the indications for treatment, the surgical procedures used, and the results of a subset of the first AMT cases carried out by the group using this nationally available supply. This user group model provides data which is different from that obtained from uncontrolled case series, or clinical trials, and may be more representative of the outcomes that can be expected when a procedure becomes widely available. Methods The first 233 AMTs, performed by the UK user group, were evaluated by audit and outcomes were assessed at 3 months. Results Of the 233 transplants, there were 126 (54.1%) valid outcome returns: the outcome for persistent epithelial defects was a healed and stable surface in 11/35 (31.4%, 95% CI 16.9 to 49.3); for chemical/thermal injuries, a healed uninflamed eye with clear cornea in 5/18 (27.8%, 95% CI 9.7 to 53.4); for bullous keratopathy a pain‐free, stable surface without bullae in 4/18 (22.2%, 95% CI 6.4 to 47.6); for ocular surface reconstruction, an epithelialised uninflamed conjunctiva without scarring in 12/23 (52.2%, 95% CI 30.6 to 73.2); and for limbal stem cell deficiency, a corneal phenotype in 4/7 (57.1%). The operative technique least associated with failure was use of a bandage contact lens at the end of the procedure (OR 0.19, 95% CI 0.06 to 0.59, p = 0.004). Previous treatment with topical steroids was significantly associated with failure (OR 5.70, 95% CI 1.77 to 18.43, p = 0.004). Conclusion Although the outcome criteria used in this study were stringent, and the follow‐up duration was short, the results of AMT by this user group were generally less favourable than those of previously reported case series. Controlled clinical trials would improve the quality of evidence for use of amniotic membrane in ocular disease. PMID:17314154

Ocular surface and tear film status among contact lens wearers and non-wearers who use VDT at work: comparing three different lens types.

PubMed

Tauste, Ana; Ronda, Elena; Baste, Valborg; Bråtveit, Magne; Moen, Bente E; Seguí Crespo, María-Del-Mar

2018-04-01

To analyze differences in the ocular surface appearance and tear film status of contact lens wearers and non-wearers in a group of visual display terminals (VDT) workers and additionally to assess differences between lens materials. Cross-sectional study of 236 office workers, of whom 92 were contact lens wearers. Workers provided information on their contact lenses (conventional hydrogel, silicone hydrogel or rigid gas permeable lenses) and exposure to VDT at work. Ocular surface and tear film status were determined by the presence of bulbar, limbal and lid redness, lid roughness and corneal staining type, and by Schirmer's and tear break-up time tests (TBUT). A generalized linear model was used to calculate the crude (cRR) and age- and sex-adjusted (aRR) relative risk to measure the association between ocular surface and tear film abnormalities and contact lens use and type. The aRR of ocular surface abnormalities was higher in contact lens wearers compared to non-wearers: bulbar redness (aRR 1.69; 95% CI 1.25-2.30), limbal redness (aRR 2.87; 1.88-4.37), lid redness (aRR 2.53; 1.35-4.73) and lid roughness (aRR 7.03; 1.31-37.82). VDT exposure > 4 h/day increased wearers' risk of limbal and lid redness. Conventional hydrogel wearers had the highest risk of ocular surface abnormalities, followed by silicone hydrogel wearers. Both contact and non-contact lens wearers had a high prevalence of altered TBUT (77.3 and 75.7% respectively) and Schirmer (51.8 and 41.3%). Regular contact lens use during VDT exposure at work increases risk of bulbar, limbal and lid redness, and lid roughness, especially in soft contact lens wearers. The high prevalence of altered TBUT and Schirmer's results in all participants suggests that VDT use greatly affects tear film characteristics.

A relatively small change in sodium chloride concentration has a strong effect on adhesion of ocular bacteria to contact lenses.

PubMed

Cowell, B A; Willcox, M D; Schneider, R P

1998-06-01

Adhesion of bacteria to hydrogel lenses is thought to be an initial step of ocular colonization allowing evasion of normal host defences. The salt concentration of media is an important parameter controlling microbial adhesion. Salinity varies from 0.97% NaCl equivalents in the open eye to 0.89% in the closed eye state. In this study, the effect of sodium chloride in the concentration range of 0.8-1.0% (w/v) NaCl on adhesion of ocular bacteria to soft contact lenses was investigated using a static adhesion assay. Pseudomonas aeruginosa was found to adhere to lenses in significantly greater amounts than Serratia marcescens, Flavobacterium meningosepticum, Stenotrophomonas maltophilia and Staphylococcus intermedius. Increasing NaCl from 0.8% to 1.0% (w/v) increased adhesion of all bacteria tested. This adhesion was strong since the organisms could not be removed by washing in low ionic buffer. Adhesion of these organisms did not correlate with their cell surface properties as determined by bacterial adhesion to hydrocarbons (BATH) and retention on sepharose columns.

Mucin gene expression is not regulated by estrogen and/or progesterone in the ocular surface epithelia of mice.

PubMed

Lange, Christine; Fernandez, Jolene; Shim, David; Spurr-Michaud, Sandra; Tisdale, Ann; Gipson, Ilene K

2003-07-01

Dry eye syndrome is prevalent in post-menopausal women, and post-menopausal women secrete less mucus in their reproductive tracts. Using a mouse model, the purpose of this study was to determine if estrogen and/or progesterone regulates Muc4 and Muc5AC gene expression in the ocular surface epithelia, as the hormones do in reproductive tract epithelia. Adult C57BL/6 mice were ovariectomized, and 19 days later, pellets containing estrogen, progesterone, or a combination were inserted subcutaneously. Ocular surface and reproductive tract tissues were harvested following seven days of hormone treatment. A control group consisted of ovariectomized mice that received no hormone treatment. Real-time reverse transcription-polymerase chain reaction was used to determine the tissue expression levels of mucin mRNA of each treatment group relative to the control. Muc4 mRNA expression levels were determined for the reproductive tract, and both Muc4 and Muc5AC expression levels were determined for the ocular surface epithelia. Muc4 and Muc5AC gene expression in ocular surface and Muc4 in reproductive tract epithelia was demonstrated by In Situ hybridization, and Muc4 and Muc5AC protein was demonstrated in the epithelia of animals in the experimental groups. The mRNA expression levels of Muc4 and Muc5AC and the immunofluorescence localization pattern in the ocular surface epithelia were not significantly different in any hormone treatment group when compared to the control ovariectomized group. By comparison, mice that were administered estrogen had a significant increase of Muc4 mRNA in the reproductive tract epithelia, progesterone given in combination with estrogen antagonized the upregulatory effects of estrogen in the reproductive tract, and the amount of Muc4 mRNA in the reproductive tract of progesterone-treated animals was not different from ovariectomized controls. Immunofluorescence localization of Muc4 in the reproductive tract epithelia of the experimental groups correlated to message levels, with lack of Muc4 protein detected in the control and progesterone groups. In comparison to reproductive tract epithelia, Muc4 and Muc5AC are not hormonally regulated by estrogen or progesterone in the ocular surface epithelia of mice. These data demonstrate that regulation of epithelial mucin genes is tissue specific.

Local synthesis of sex hormones: are there consequences for the ocular surface and dry eye?

PubMed

Gibson, Emma J; Stapleton, Fiona; Wolffsohn, James S; Golebiowski, Blanka

2017-12-01

Sex hormones are associated with the physiology and pathophysiology of almost all organs in the body, as well as most diseases. Interest in the associations between sex hormones and ocular tissues has increased in recent years. Androgens may have a positive effect on dry eye, whereas the effects of oestrogen on ocular conditions remain unclear. Intracrinology, the local synthesis and metabolism of hormones that is unique to humans, is of relevance to the eye and may help to explain why studies of the relationship between oestrogens and dry eye signs and symptoms are inconclusive. Knowledge of the pathways of hormone formation and metabolism is crucial to understanding the pathogenesis of ocular disease including dry eye. This review examines the mechanisms of steroidal sex hormone biosynthesis and reviews the significance of locally produced sex hormones, with a focus on ocular surface tissues. Much of the current literature is based on animal studies, which may not be transferable to humans due to the absence of intracrine production in animals. A large proportion of the human studies investigate systemic hormone levels rather than local levels. There is subsequently a need for additional studies to provide a better understanding of the local production of sex hormones within the human eye and ocular surface and to clarify the relationships between ocular levels of sex hormones and conditions including dry eye. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Zika virus infection of cellular components of the blood-retinal barriers: implications for viral associated congenital ocular disease.

PubMed

Roach, Tracoyia; Alcendor, Donald J

2017-03-03

Ocular abnormalities present in microcephalic infants with presumed Zika virus (ZIKV) congenital disease includes focal pigment mottling of the retina, chorioretinal atrophy, optic nerve abnormalities, and lens dislocation. Target cells in the ocular compartment for ZIKV infectivity are unknown. The cellular response of ocular cells to ZIKV infection has not been described. Mechanisms for viral dissemination in the ocular compartment of ZIKV-infected infants and adults have not been reported. Here, we identify target cells for ZIKV infectivity in both the inner and outer blood-retinal barriers (IBRB and OBRB), describe the cytokine expression profile in the IBRB after ZIKV exposure, and propose a mechanism for viral dissemination in the retina. We expose primary cellular components of the IBRB including human retinal microvascular endothelial cells, retinal pericytes, and Müller cells as well as retinal pigmented epithelial cells of the OBRB to the PRVABC56 strain of ZIKV. Viral infectivity was analyzed by microscopy, immunofluorescence, and reverse transcription polymerase chain reaction (RT-PCR and qRT-PCR). Angiogenic and proinflammatory cytokines were measured by Luminex assays. We find by immunofluorescent staining using the Flavivirus 4G2 monoclonal antibody that retinal endothelial cells and pericytes of the IBRB and retinal pigmented epithelial cells of the OBRB are fully permissive for ZIKV infection but not Müller cells when compared to mock-infected controls. We confirmed ZIKV infectivity in retinal endothelial cells, retinal pericytes, and retinal pigmented epithelial cells by RT-PCR and qRT-PCR using ZIKV-specific oligonucleotide primers. Expression profiles by Luminex assays in retinal endothelial cells infected with ZIKV revealed a marginal increase in levels of beta-2 microglobulin (β2-m), granulocyte macrophage colony-stimulating factor (GMCSF), intercellular adhesion molecule 1 (ICAM-1), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP1), and vascular cell adhesion molecule 1 (VCAM-1) and higher levels of regulated upon activation, normal T cell expressed and presumably secreted (RANTES) but lower levels of interleukin-4 (IL-4) compared to controls. Retinal endothelial cells, retinal pericytes, and retinal pigmented epithelial cells are fully permissive for ZIKV lytic replication and are primary target cells in the retinal barriers for infection. ZIKV infection of retinal endothelial cells and retinal pericytes induces significantly higher levels of RANTES that likely contributes to ocular inflammation.

Preservative-free treatment in glaucoma: who, when, and why.

PubMed

Stalmans, Ingeborg; Sunaric Mégevand, Gordana; Cordeiro, M Francesca; Hommer, Anton; Rossetti, Luca; Goñi, Francisco; Heijl, Anders; Bron, Alain

2013-01-01

To review and summarize the available literature on the effect of preservatives on the eye, to provide practical guidance for the clinical assessment of the ocular surface in glaucoma patients, and to define patient populations that might benefit from preservative-free topical intraocular pressure (IOP)-lowering agents. This manuscript is based on a combination of a literature review on preservatives and the eye and expert opinion from glaucoma specialists with an interest in ocular surface disease. There is an increasingly recognized association between eyedrop preservatives and ocular surface disease. Preservative-free therapy is now available for a wide range of active compounds, although there are still some misconceptions regarding their appropriate use. For patients treated topically for glaucoma or ocular hypertension, a rough estimate could be that 20% may need treatment with topical IOP-reducing agents that are free from preservatives. This review provides an up-to-date account of the literature regarding preservatives and the eye, as well as suggestions and recommendations on to when to use preservative-free antiglaucoma treatment.

Therapeutic use of mini-scleral lenses in a patient with Graves' ophthalmopathy.

PubMed

Harthan, Jennifer S

2014-01-01

Patients with Graves' ophthalmopathy can be very challenging to manage secondary to the complex nature of their disease presentation. Patients may present with a variety of ocular findings including: lid retraction, periorbital and lid swelling, chemosis, conjunctival hyperemia, proptosis, optic neuropathy, restrictive myopathy, exposure keratopathy and/or keratoconjunctivitis sicca. Mini-scleral and scleral lens designs have been important in the management of irregular and regular corneas, and in the therapy of ocular surface diseases. We present here the case of a 48-year-old Caucasian male who had been diagnosed with Graves' ophthalmopathy 13 years earlier. With significant ocular surface staining and over ten diopters of astigmatism, the patient had never been able to wear contact lenses comfortably. After being fit with the Mini-Scleral Design™ lenses, his vision improved to 20/25 OU, his ocular surface improved, and overall quality of vision increased. Copyright © 2012 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.

Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells and Tissues Following Combat Associated Trauma

DTIC Science & Technology

2013-09-01

death pathways such as apoptosis subsequent to acute trauma as soon as possible, ideally by self- administration of a drug or a biologic that can be... Drugs to Ocular Tissues Including Retina and Cornea . Mol Ther, 2007;16(1):107- 14. 3. Read SP, Cashman SM, and Kumar-Singh R: POD...1 AD_________________ Award Number: W81XWH-12-1-0374 TITLE: Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells

Comparison of in vivo efficacy of different ocular lubricants in dry eye animal models.

PubMed

Zheng, Xiaodong; Goto, Tomoko; Ohashi, Yuichi

2014-04-29

To compare the efficacy of three types of ocular lubricants in protecting corneal epithelial cells in dry eye animal models. Ocular lubricants containing 0.1% or 0.3% sodium hyaluronate (SH), carboxymethylcellulose (CMC), or hydroxypropyl methylcellulose (HPMC) were tested. First, ocular lubricant containing 0.002% fluorescein was dropped onto the rabbit corneas. The fluorescein intensity as an index of retention was measured. Second, a rabbit dry eye model was made by holding the eye open with a speculum, and 50 μL of each ocular lubricant was dropped onto the cornea. After 3 hours, the corneas were stained with 1% methylene blue (MB), and the absorbance of MB was measured. Third, a rat dry eye model was treated with the ocular lubricants for 4 weeks, and the corneal fluorescein staining was scored. Eyes treated with physiological saline were used as controls. Finally, immunohistochemistry was used to analyze occludin, an epithelial barrier protein, in cultured human corneal epithelial cells pretreated with ocular lubricants and desiccated for 20 or 60 minutes. Our results showed that 0.3% SH had a significantly longer retention time than the other lubricants (all P < 0.01). The absorbance of MB was significantly lower in the 0.3% SH group. The corneas of rats exposed to 0.3% SH had significantly lower fluorescein staining scores. A significantly higher number of occludin-positive cells were found after exposure to 0.3% SH than other lubricants. Ocular lubricant containing 0.3% SH would be preferable to treat patients with dry eye syndrome. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Translational Immuno- and Neuro-imaging Demonstrate Corneal Neuro-immune Crosstalk

PubMed Central

Hamrah, Pedram; Seyed-Razavi, Yashar; Yamaguchi, Takefumi

2017-01-01

Corneal immuno- and neuro-imaging approaches facilitate in vivo analyses of the cornea, including high-resolution imaging of corneal immune cells and nerves. This approach facilitates the analyses of underlying immune and nerve alterations not detected by clinical slit-lamp examination alone. In this review, we describe recent work performed in our translational ocular immunology center with a focus on ‘bench-to-bedside’ and ‘bedside-to-bench’ research. The ability to visualize dendritiform immune cells (DCs) in patients with laser in vivo confocal microscopy (IVCM), recently discovered in the central murine cornea, has allowed us to demonstrated their utility as a potential surrogate biomarker for inflammatory ocular surface diseases. This biomarker for inflammation allows the measurement of therapeutic efficacy of anti-inflammatory drugs and its utility as an endpoint in clinical trials with high inter-observer agreement. IVCM image analyses from our studies demonstrated a significant increase in DC density and size in ocular disease, a positive correlation between DC density and clinical signs and symptoms of disease and pro-inflammatory tear cytokines, and a strong negative correlation between DC density and subbasal nerve density. In conjunction with pre-clinical research investigating the inflammatory state in a partial or fully denervated cornea, our results indicated that corneal nerves are directly involved in the regulation of homeostasis and immune privilege in the cornea. PMID:27631352

Insects have hairy eyes that reduce particle deposition

NASA Astrophysics Data System (ADS)

Amador, G. J.; Durand, F.; Mao, W.; Pusulri, S.; Takahashi, H.; Nguyen, V.-T.; Shimoyama, I.; Alexeev, A.; Hu, D. L.

2015-12-01

An insect's eyes may make up to 40% of its body's surface, and are in danger of being coated by foreign particles such as dust and pollen. To protect them, several insect species possess an array of ocular hairs evenly spaced between each photoreceptor unit. Although these hairs have been observed for over 50 years, their purpose remains a mystery. In this study, we elucidate the function of ocular hairs using a combination of experiments, numerical simulation and micro-fabrication. We measure the eyes of 18 species of insects and find that the length of their ocular hairs is equal to their spacing. We conduct wind tunnel experiments using both an insect eye mimic and an at-scale fabricated micro-pillar array of the same dimensions as the insect eye. Our experiments and simulations show that ocular hairs reduce airflow at the eye surface by up to 90%. We conclude that ocular hairs act similarly to mammalian eyelashes: as insects fly, ocular hairs deflect incoming air and create a zone of stagnant air. Airflow and particle deposition are reduced dramatically, while light is only minimally occluded. Micro-scale ocular hairs may find application in the deployment of sensors outdoors, for which accumulation of airborne dust and pollen has no current solution.

A MODEL FOR THE TEAR FILM AND OCULAR SURFACE TEMPERATURE FOR PARTIAL BLINKS

PubMed Central

Deng, Quan; Braun, R. J.; Driscoll, T. A.; King-Smith, P. E.

2015-01-01

In this paper, we investigate the dynamics of tear film and the associated temperature variation for partial blinks. We investigate the mechanism of fluid supply during partial blink cycles, and compare the film thickness with observation in vivo. We find that varying the thickness of the fluid layer beneath the moving upper lid improves the agreement for the in vivo measurement of tear film thickness after a half blink. By examining the flux of the fluid, we provide an explanation of this assumption. We also investigate the temperature dynamics both at the ocular surface and inside the simulated anterior chamber. Our simulation results suggest that the ocular surface temperature readjusts rapidly to normal temperature distribution after partial blinks. PMID:25635242

The controlled-environment chamber: a new mouse model of dry eye.

PubMed

Barabino, Stefano; Shen, Linling; Chen, Lu; Rashid, Saadia; Rolando, Maurizio; Dana, M Reza

2005-08-01

To develop a controlled-environment chamber (CEC) for mice and verify the effects of a low-humidity setting on ocular surface signs in normal mice. Eight- to 12-week-old BALB/c mice were used in a controlled-environment chamber (CEC) where relative humidity (RH), temperature (T), and airflow (AF) are regulated and monitored. Mice were placed into the CEC and exposed to specific environmentally controlled conditions (RH = 18.5% +/- 5.1%, AF = 15 L/min, T = 21-23 degrees C) for 3, 7, 14, and 28 days. Control mice were kept in a normal environment (RH = 50%-80%, no AF, T = 21-23 degrees C) for the same duration. Aqueous tear production by means of the cotton thread test, corneal fluorescein staining (score, 0-15), and goblet cell density in the superior and inferior conjunctiva were measured by a masked observer. No statistically significant differences between the groups were found at baseline. Decreased tear secretion and increased corneal fluorescein staining were significantly present on day 3, 7, 14, and 28 in animals kept in the CEC. Goblet cell density was significantly decreased in the superior conjunctiva on day 7, and on day 3, 7, and 14 in the inferior conjunctiva in the CEC-kept mice compared with control animals. This study indicates that exposure of normal mice to a low-humidity environment in a CEC can lead to significant alterations in tear secretion, goblet cell density, and acquisition of dry eye-related ocular surface signs.

Fibroblast growth factor 10 upregulates the expression of mucins in rat conjunctival epithelial cells

PubMed Central

Ma, Mingming; Zhang, Zhengwei; Niu, Weiran; Zheng, Wenjing; Kelimu, Jiang

2011-01-01

Purpose This in vitro study aimed to gain insight into the function of fibroblast growth factor 10 (FGF10) on the ocular surface, especially its effect on mRNA expression of the mucins Muc1, Muc4, and Muc5ac, and mucin protein synthesis. Methods We isolated primary cultured rat conjunctival epithelial cells (Cj-ECs) and treated them with FGF10 (1 ng/ml, 10 ng/ml, 100 ng/ml, and 200 ng/ml) and basic fibroblast growth factor 2 (FGF2; 10 ng/ml) for 24 h or 48 h. The proliferation of Cj-ECs was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). mRNA levels of Muc1, Muc4, and Muc5ac were determined by real-time PCR. Synthesis levels of MUC1 and MUC4 were measured by western blot. Flow cytometry and Annexin V/PI double staining revealed degrees of apoptosis. Results In primary culture, the epithelial cells were compact and cobblestone pavement in shape. Most of the cells were positive for cytokeratin (CK). FGF10 and FGF2 significantly stimulated Muc1, Muc4, and Muc5ac mRNA expression, cell proliferation, and synthesis of MUC1 and MUC4 proteins. FGF10 was more potent than FGF2 in these regards. FGF10 did not restrain the apoptosis of Cj-ECs. Conclusions The results of this study demonstrated that FGF10 is associated with the promotion of Cj-EC proliferation and mucin production. The effects of FGF10 on Cj-ECs support a rationale to investigate its therapeutic potential for ocular surface diseases. PMID:22065934

Bioengineered Lacrimal Gland Organ Regeneration in Vivo

PubMed Central

Hirayama, Masatoshi; Tsubota, Kazuo; Tsuji, Takashi

2015-01-01

The lacrimal gland plays an important role in maintaining a homeostatic environment for healthy ocular surfaces via tear secretion. Dry eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye disorders and causes ocular discomfort, significant visual disturbances, and a reduced quality of life. Current therapies for dry eye disease, including artificial tear eye drops, are transient and palliative. The lacrimal gland, which consists of acini, ducts, and myoepithelial cells, develops from its organ germ via reciprocal epithelial-mesenchymal interactions during embryogenesis. Lacrimal tissue stem cells have been identified for use in regenerative therapeutic approaches aimed at restoring lacrimal gland functions. Fully functional organ replacement, such as for tooth and hair follicles, has also been developed via a novel three-dimensional stem cell manipulation, designated the Organ Germ Method, as a next-generation regenerative medicine. Recently, we successfully developed fully functional bioengineered lacrimal gland replacements after transplanting a bioengineered organ germ using this method. This study represented a significant advance in potential lacrimal gland organ replacement as a novel regenerative therapy for dry eye disease. In this review, we will summarize recent progress in lacrimal regeneration research and the development of bioengineered lacrimal gland organ replacement therapy. PMID:26264034

Biofilms in Infections of the Eye

PubMed Central

Bispo, Paulo J. M.; Haas, Wolfgang; Gilmore, Michael S.

2015-01-01

The ability to form biofilms in a variety of environments is a common trait of bacteria, and may represent one of the earliest defenses against predation. Biofilms are multicellular communities usually held together by a polymeric matrix, ranging from capsular material to cell lysate. In a structure that imposes diffusion limits, environmental microgradients arise to which individual bacteria adapt their physiologies, resulting in the gamut of physiological diversity. Additionally, the proximity of cells within the biofilm creates the opportunity for coordinated behaviors through cell–cell communication using diffusible signals, the most well documented being quorum sensing. Biofilms form on abiotic or biotic surfaces, and because of that are associated with a large proportion of human infections. Biofilm formation imposes a limitation on the uses and design of ocular devices, such as intraocular lenses, posterior contact lenses, scleral buckles, conjunctival plugs, lacrimal intubation devices and orbital implants. In the absence of abiotic materials, biofilms have been observed on the capsule, and in the corneal stroma. As the evidence for the involvement of microbial biofilms in many ocular infections has become compelling, developing new strategies to prevent their formation or to eradicate them at the site of infection, has become a priority. PMID:25806622

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

PubMed

Smith, Andrew; Pawar, Mercy; Van Dort, Marcian E; Galbán, Stefanie; Welton, Amanda R; Thurber, Greg M; Ross, Brian D; Besirli, Cagri G

2018-04-30

ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168. Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes. Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901. Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.

Effect of 0.3% Hydroxypropyl Methylcellulose/Dextran Versus 0.18% Sodium Hyaluronate in the Treatment of Ocular Surface Disease in Glaucoma Patients: A Randomized, Double-Blind, and Controlled Study.

PubMed

Prabhasawat, Pinnita; Ruangvaravate, Ngamkae; Tesavibul, Nattaporn; Thewthong, Maneerat

2015-01-01

To compare the efficacy and safety of 0.3% hydroxypropyl methylcellulose/dextran (HPMC/dextran) and 0.18% sodium hyaluronate (SH) in the treatment of ocular surface disease in patients using antiglaucoma drugs containing preservatives. This was a double-blind, randomized, parallel-group study in 70 glaucoma patients with Ocular Surface Disease Index (OSDI) score greater than 20 points and/or presence of ocular signs. Patients were randomized to receive either preservative-free 0.3% HPMC/dextran (n=35) or preservative-free 0.18% SH (n=35). Treatment was 1 drop in each eye, 4 times a day. Data were collected at baseline, at day 7 and day 28. The groups were homogeneous at baseline. At day 28, both treatments showed significant improvements (P<0.05) in the mean OSDI score, lid skin and lid margin inflammation, conjunctival injection, and expressibility of meibomian glands, corneal staining score, fluorescein tear breakup time (FBUT), and Schirmer I test. However, the mean OSDI score, lid margin inflammation and conjunctival injection showed significant improvements (P<0.05) in the SH group at days 7 and 28, compared to the HPMC/dextran group. FBUT and the Schirmer I test also showed significant improvements (P<0.05) in the SH group compared to the HPMC/dextran group, at day 28. No adverse reactions were observed in either group. Preservative-free artificial tear, 0.3% HPMC/dextran, and 0.18% SH, caused a significant relief of the ocular surface disease in glaucoma patients. However, 0.18% SH led to a greater improvement in ocular signs and symptoms than 0.3% HPMC/dextran.

Tear Osmolarity and Correlation With Ocular Surface Parameters in Patients With Dry Eye.

PubMed

Mathews, Priya M; Karakus, Sezen; Agrawal, Devika; Hindman, Holly B; Ramulu, Pradeep Y; Akpek, Esen K

2017-11-01

To analyze the distribution of tear film osmolarity in patients with dry eye and its association with other ocular surface parameters. Tear osmolarity and other quantitative dry eye parameters were obtained from patients with 1) clinically significant dry eye (significant symptoms and ocular surface staining, n = 131), 2) symptoms-only dry eye (significant symptoms but no significant ocular surface staining, n = 52), and 3) controls (no significant symptoms or staining, n = 42). Tear osmolarity varied significantly across groups (P = 0.01), with patients with clinically significant dry eye having the highest tear osmolarity (312.0 ± 16.9 mOsm/L), control patients having the lowest tear osmolarity (305.6 ± 9.7 mOsm/L), and patients with symptoms-only dry eye falling in between (307.4 ± 5.6 mOsm/L). Patients with clinically significant dry eye also tended to have a greater intereye difference in osmolarity (12.0 ± 13.4) than did the individuals with symptoms-only dry eye (9.1 ± 12.4) and controls (9.0 ± 7.4) (P = 0.06). In multivariable regression models, higher tear osmolarity was associated with higher Ocular Surface Disease Index, discomfort subscore (P = 0.02), and higher corneal and conjunctival staining scores (P < 0.01 for both). Worse eye tear osmolarity was not correlated with the corresponding tear film breakup time or Schirmer test (P > 0.05 for both). Individuals with symptomatic dry eye that is not yet clinically significant seem to have higher and more variable osmolarity measurements than controls, potentially indicating that changes in osmolarity precede clinical findings.

Anterior Corneal, Posterior Corneal, and Lenticular Contributions to Ocular Aberrations.

PubMed

Atchison, David A; Suheimat, Marwan; Mathur, Ankit; Lister, Lucas J; Rozema, Jos

2016-10-01

To determine the corneal surfaces and lens contributions to ocular aberrations. There were 61 healthy participants with ages ranging from 20 to 55 years and refractions -8.25 diopters (D) to +3.25 D. Anterior and posterior corneal topographies were obtained with an Oculus Pentacam, and ocular aberrations were obtained with an iTrace aberrometer. Raytracing through models of corneas provided total corneal and surface component aberrations for 5-mm-diameter pupils. Lenticular contributions were given as differences between ocular and corneal aberrations. Theoretical raytracing investigated influence of object distance on aberrations. Apart from defocus, the highest aberration coefficients were horizontal astigmatism, horizontal coma, and spherical aberration. Most correlations between lenticular and ocular parameters were positive and significant, with compensation of total corneal aberrations by lenticular aberrations for 5/12 coefficients. Anterior corneal aberrations were approximately three times higher than posterior corneal aberrations and usually had opposite signs. Corneal topographic centers were displaced from aberrometer pupil centers by 0.32 ± 0.19 mm nasally and 0.02 ± 0.16 mm inferiorly; disregarding corneal decentration relative to pupil center was significant for oblique astigmatism, horizontal coma, and horizontal trefoil. An object at infinity, rather than at the image in the anterior cornea, gave incorrect aberration estimates of the posterior cornea. Corneal and lenticular aberration magnitudes are similar, and aberrations of the anterior corneal surface are approximately three times those of the posterior surface. Corneal decentration relative to pupil center has significant effects on oblique astigmatism, horizontal coma, and horizontal trefoil. When estimating component aberrations, it is important to use correct object/image conjugates and heights at surfaces.

Long-term outcomes after adjunctive topical 5-flurouracil or mitomycin C for the treatment of surgically excised, localized ocular surface squamous neoplasia.

PubMed

Bahrami, Bobak; Greenwell, Timothy; Muecke, James S

2014-01-01

To report rates of recurrence and complications of localized ocular surface squamous neoplasia treated with 5-fluorouracil or mitomycin C as adjunctive treatment to surgical excision. Long-term follow up of two prospective, non-comparative interventional case series. One hundred fifty-three eyes with histologically confirmed localized, non-invasive ocular surface squamous neoplasia. 89 eyes were treated with adjuvant 5-fluorouracil and 64 eyes were treated with adjuvant mitomycin C. Following surgical excision±cryotherapy patients received topical 5-fluorouracil 1% four times daily for two weeks or topical mitomycin C 0.04% four times daily for two to three 1-week cycles. Ocular surface squamous neoplasia recurrence, complications of therapy and compliance. Median follow up was 33.6 (range 12-84) months and 57.9 (range 12-160) months in 5-fluorouracil and mitomycin C groups, respectively. There was one recurrence in the 5-fluorouracil group and no recurrences in the mitomycin C group. Side-effects occurred in 69% of 5-fluorouracil patients and 41% of mitomycin C patients. Five patients (6%) required intervention for treatment-related side-effects in the 5-fluorouracil group versus 11 (17%) in the mitomycin C group. No vision-threatening complications were noted. Long-term recurrence of localised ocular surface squamous neoplasia is rare when topical 5-fluorouracil or mitomycin C are used as adjunctive treatment to surgical excision. While side-effects are common, the majority are transient and rarely limit compliance. © 2013 Royal Australian and New Zealand College of Ophthalmologists.

Topically applied 1% voriconazole induces dysplastic changes on the ocular surface: animal study.

PubMed

Arikan, Gul; Karatas, Ezgi; Lebe, Banu; Ayhan, Ziya; Utine, Canan Asli; Kutsoylu, Oya Eren; Gunenc, Uzeyir; Yilmaz, Osman

2018-04-26

To identify the risk of inducing ocular surface dysplasia following topical administration of 1% voriconazole eye drop. Fourteen noninflamed healthy eyes of 14 white adult New Zealand rabbits were included in the study. The rabbits were randomly divided into two groups comprised of 7 rabbits each. Group 1 received topical 1% voriconazole and Group 2 received topical saline as the control group. In all animals, right eye was selected for the study. In Group 1 (Voriconazole Group), single drop of voriconazole was instilled every 10 min consecutively for 17 times a day for 60 days. In Group 2 (Control Group), single drop of saline was instilled every 10 min consecutively for 17 times a day for 60 days. At two months, animals were sacrificed and study eyes were enucleated with the eyelids. The specimens were stained with hematoxylin-eosin and histopathologic changes in cornea, bulbar and palpebral conjunctiva were evaluated under light microscope. There were no macroscopically visible lesions on the ocular surface of any rabbits. Histopathological evaluation showed mild to moderate dysplasia localized mainly in the limbus and extending to the adjacent cornea and bulbar conjunctiva in all rabbits in Voriconazole Group. Severe dysplasia or carcinoma in situ was not observed. In the Control Group, dysplasia was not observed, at all. This animal study provides a possible relationship between topically administered 1% voriconazole and ocular surface dysplasia. We recommend ophthalmologists to be aware of the risk of ocular surface dysplasia in patients received voriconazole eye drop.

Relevance of Lipid-Based Products in the Management of Dry Eye Disease.

PubMed

Garrigue, Jean-Sébastien; Amrane, Mourad; Faure, Marie-Odile; Holopainen, Juha M; Tong, Louis

2017-11-01

Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air-water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed.

Thermal fluctuation based study of aqueous deficient dry eyes by non-invasive thermal imaging.

PubMed

Azharuddin, Mohammad; Bera, Sumanta Kr; Datta, Himadri; Dasgupta, Anjan Kr

2014-03-01

In this paper we have studied the thermal fluctuation patterns occurring at the ocular surface of the left and right eyes for aqueous deficient dry eye (ADDE) patients and control subjects by thermal imaging. We conducted our experiment on 42 patients (84 eyes) with aqueous deficient dry eyes and compared with 36 healthy volunteers (72 eyes) without any history of ocular surface disorder. Schirmer's test, Tear Break-up Time, tear Meniscus height and fluorescein staining tests were conducted. Ocular surface temperature measurement was done, using an FL-IR thermal camera and thermal fluctuation in left and right eyes was calculated and analyzed using MATLAB. The time series containing the sum of squares of the temperature fluctuation on the ocular surface were compared for aqueous deficient dry eye and control subjects. Significant statistical difference between the fluctuation patterns for control and ADDE was observed (p < 0.001 at 95% confidence interval). Thermal fluctuations in left and right eyes are significantly correlated in controls but not in ADDE subjects. The possible origin of such correlation in control and lack of correlation in the ADDE subjects is discussed in the text. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of Dry Eye and Meibomian Gland Dysfunction in Teenagers with Myopia through Noninvasive Keratograph

PubMed Central

Wang, Xiu; Lu, Xiaoxiao; Yang, Jun; Wei, Ruihua; Yang, Liyuan; Zhao, Shaozhen; Wang, Xilian

2016-01-01

Purpose. This study aims to evaluate dry eye and ocular surface conditions of myopic teenagers by using questionnaire and clinical examinations. Methods. A total of 496 eyes from 248 myopic teenagers (7–18 years old) were studied. We administered Ocular Surface Disease Index (OSDI) questionnaire, slit-lamp examination, and Keratograph 5M. The patients were divided into 2 groups based on OSDI dry eye standard, and their ocular surfaces and meibomian gland conditions were evaluated. Results. The tear meniscus heights of the dry eye and normal groups were in normal range. Corneal fluorescein scores were significantly higher whereas noninvasive break-up time was dramatically shorter in the dry eye group than in the normal group. All three meibomian gland dysfunction parameters (i.e., meibomian gland orifice scores, meibomian gland secretion scores, and meibomian gland dropout scores) of the dry eye group were significantly higher than those of the normal group (P < 0.0001). Conclusions. The prevalence of dry eye in myopic teenagers is 18.95%. Meibomian gland dysfunction plays an important role in dry eye in myopic teenagers. The Keratograph 5M appears to provide an effective noninvasive method for assessing ocular surface situation of myopic teenagers. PMID:26881059

Ultra High-Resolution Anterior Segment Optical Coherence Tomography in the Diagnosis and Management of Ocular Surface Squamous Neoplasia

PubMed Central

Thomas, Benjamin J.; Galor, Anat; Nanji, Afshan A.; Sayyad, Fouad El; Wang, Jianhua; Dubovy, Sander R.; Joag, Madhura G.; Karp, Carol L.

2014-01-01

The development of optical coherence tomography (OCT) technology has helped to usher in a new era of in vivo diagnostic imaging of the eye. The utilization of OCT for imaging of the anterior segment and ocular surface has evolved from time-domain devices to spectral-domain devices with greater penetrance and resolution, providing novel images of anterior segment pathology to assist in diagnosis and management of disease. Ocular surface squamous neoplasia (OSSN) is one such pathology that has proven demonstrable by certain anterior segment OCT machines, specifically the newer devices capable of performing ultra high-resolution OCT (UHR-OCT). Distinctive features of OSSN on high resolution OCT allow for diagnosis and differentiation from other ocular surface pathologies. Subtle findings on these images help to characterize the OSSN lesions beyond what is apparent with the clinical examination, providing guidance for clinical management. The purpose of this review is to examine the published literature on the utilization of UHR-OCT for the diagnosis and management of OSSN, as well as to report novel uses of this technology and potential directions for its future development. PMID:24439046

Tear film aberration dynamics and vision-related quality of life in patients with dry eye disease.

PubMed

Denoyer, Alexandre; Rabut, Ghislaine; Baudouin, Christophe

2012-09-01

Corneal and ocular wavefront aberrations were recorded together with clinical examination results and patient-reported vision-related quality-of-life evaluation results to define the relevance of dynamic optical analysis of the eye in dry eye disease (DED). Prospective and comparative clinical study. Forty DED patients and 40 age- and gender-matched control subjects. Serial measurements of ocular and corneal higher-order aberrations (HOAs) after blink were performed for 10 seconds using the KR-1 aberrometer (Topcon, Clichy, France). Vision-related health-targeted quality of life was evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. The clinical examination included tear film assessment (tear film break-up time and Schirmer I test), ocular surface damage assessment with the Oxford and van Bijsterveld indexes, and Meibomian dysfunction grading. Tear osmolarity also was measured. The time course of HOAs and modulation transfer function (MTF) was compared between groups and was analyzed in comparison with the OSDI and clinical data in DED patients. The root mean square of ocular and corneal total HOAs, particularly third-order aberrations, significantly increased over the 10-second period in DED patients, whereas no change occurred in controls. Analysis of MTF revealed progressive degradation of ocular optical quality resulting from loss of contrast at intermediate and high spatial frequencies in DED patients compared with controls. The progression index for corneal HOAs was correlated with the subjective index of patient-reported visual outcomes and with objective clinical findings of tear film and ocular surface damage. Objective measurement of the time course of HOAs may constitute a new single instrument to evaluate and manage patients with DED because it reliably reflects the completeness of the disease. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Eye cosmetic usage and associated ocular comfort.

PubMed

Ng, Alison; Evans, Katharine; North, Rachel; Purslow, Christine

2012-11-01

Eye cosmetics usage is commonplace and whilst some products such as eyeliner are applied with close proximity to the ocular surface, there is little knowledge of the short- and long-term ocular effects of eye cosmetic formulations. This study aimed to investigate the use of eye cosmetics and identify any relationships between ocular comfort and cosmetic usage. Results were collated from an online survey comprising 23 questions that recorded demographics, Ocular Surface Disease Index (OSDI) score, extent and range of eye cosmetic use and perceived comfort differences with and without eye cosmetics. The 1360 female respondents (median age 25, interquartile range 20-34 years) completed the survey; 83% reported using eye cosmetics regularly (≥ 3 times per week) with mascara being most commonly used. Fifty three per cent used at least three different eye cosmetics products regularly. OSDI scores of cosmetics users were similar to non-users (p = 0.083), but perceived comfort was greater when cosmetics were not used (p < 0.001). In occasional cosmetics users (use of products < 3 times per week), 65% reported a reduction in comfort when cosmetics were used. Median OSDI scores suggested a trend towards reduced comfort amongst eyeliner users (p = 0.07) although frequency and type of cosmetic products used did not appear to influence OSDI scores. This study shows the use of multiple eye cosmetics is extensive and associated with the perception of ocular discomfort. With such widespread use of these products, more research is required to assess the effect on the ocular surface and tear film, which may be underestimated. Ophthalmic & Physiological Optics © 2012 The College of Optometrists.

Rapidly fatal nasal natural killer/T-cell lymphoma: orbital and ocular adnexal presentations.

PubMed

Yousuf, Salman J; Kumar, Nitin; Kidwell, Earl D; Copeland, Robert A

2011-03-01

Nasal natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy that may initially present with orbital and/or ocular adnexal symptoms. We describe the case of a 27-year-old female with nasal NKTL, who initially presented with epiphora and died 4 months thereafter.

Progressive replacement of oral mucosa by conjunctiva in osteo-odonto-keratoprosthesis: preliminary observations.

PubMed

Pecorella, Irene; Maurizio, Taloni; Antonio, Ciardi; Giancarlo, Falcinelli

2006-02-01

In a Strampelli osteo-odonto-keratoprosthesis, a patch of oral mucosa is frequently used to cover the ocular surface after implantation of an osteodental lamina into the eye. In many cases, gross modifications in the eye covering become apparent a few years later. The aim of this study was to investigate the histologic findings in the clinically modified ocular surface. Biopsies were performed in 7 patients at the junction between the osteodental acrylic lamina and surrounding modified oral mucosa, during surgery for local plastic reconstruction or positioning of antiglaucoma silicone tubes. Specimens were examined by light microscopy. Six of the 7 clinically modified specimens corresponded microscopically to conjunctiva. Typical oral mucosa could still be observed overlying the osteodental acrylic lamina. The production of local regulatory factors is a possible explanation for the survival of oral mucosa over the osteodental acrylic lamina, whereas their absence in distant areas may have induced the oral mucosa to transdifferentiate into a conjunctival-type lining. Alternatively, conjunctival regrowth from forniceal stem cells should be taken into consideration.

Are linear AChR epitopes the real culprit in ocular myasthenia gravis?

PubMed

Wu, Xiaorong; Tüzün, Erdem

2017-02-01

Extraocular muscle weakness occurs in most of the myasthenia gravis (MG) patients and it is often the initial complaint. Approximately 10-20% of MG patients with extraocular muscle weakness display only ocular symptoms and rest of the patients subsequently develop generalized muscle weakness. It is not entirely clear why some MG patients develop only ocular symptoms and why extraocular muscle weakness almost always precedes generalized muscle weakness. These facts are often explained by increased susceptibility of extraocular muscles due to their reduced endplate safety factor and lower complement inhibitor expression. Findings of a recently developed animal model of ocular MG suggest that additional factors might be in play. While immunization of HLA transgenic and wild-type (WT) mice with the native acetylcholine receptor (AChR) pentamer carrying conformational epitopes generates severe generalized muscle weakness, immunization of the same mouse strains with recombinant unfolded AChR subunits containing linear epitopes induces ptosis with or without mild generalized muscle weakness. Notably, immunization of mice with deficient T helper cell-mediated antigen presentation with recombinant AChR subunits or whole native AChR pentamer also induces ocular symptoms, AChR-reactive B cells and AChR antibodies. Based on these findings, we hypothesize that ocular symptoms observed in the earlier stages of MG might be triggered by linear and non-conformational AChR epitopes expressed by thymic cells or invading microorganisms. This initial AChR autoimmunity might be managed by T cell-independent and B cell mediated mechanisms yielding low affinity AChR antibodies. These antibodies are putatively capable of inducing muscle weakness only in extraocular muscles which have increased vulnerability due to their inherent biological properties. After this initial attack, as AChR bearing immune complexes form and the immune system gains access to the native AChR expressed by muscle and thymic myoid cells, a more robust anti-AChR autoimmunity develops giving way to high affinity AChR antibodies, thymic germinal center formation and severe generalized muscle weakness. Accurate characterization of chain if events leading to ocular and generalized symptoms in MG might enable development of novel therapeutics that might prevent the transition from mild ocular symptoms to severe generalized weakness in earlier stages of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effect of Tear Supplementation with 0.15% Preservative-Free Zinc-Hyaluronate on Ocular Surface Sensations in Patients with Dry Eye.

PubMed

Perényi, Kristóf; Dienes, Lóránt; Kornafeld, Anna; Kovács, Balázs; Kiss, Huba J; Szepessy, Zsuzsanna; Nagy, Zoltán Z; Barsi, Árpád; Acosta, M Carmen; Gallar, Juana; Kovács, Illés

To evaluate the effect of tear supplementation with preservative free 0.15% zinc-hyaluronate on ocular surface sensations and corneal sensitivity in dry eye patients. Ocular surface sensations were assessed using the ocular surface disease index (OSDI) questionnaire and by recording ocular sensations during forced blinking in parallel with noninvasive tear film breakup time measurement in 20 eyes of 20 dry eye patients. Corneal sensitivity thresholds to selective stimulation of corneal mechano-, thermal- and chemical receptors were measured using the Belmonte gas esthesiometer. All baseline measurements were repeated after 1 month of treatment with 0.15% zinc-hyaluronate. After 1 month, a significant decrease in mean OSDI score (from 35.66 ± 12.36 to 15.03 ± 11.22; P < 0.001) and a significant improvement in tear film breakup time (from 3.83 ± 0.80 to 8.67 ± 4.50 s; P < 0.001) was observed compared to baseline. Sensory responses during the interblink period also significantly decreased after 1 month (P < 0.004). Corneal sensitivity thresholds to mechanical stimulation (90.61 ± 20.35 vs. 103.92 ± 17.97 mL/min; P < 0.025) and chemical stimulation (33.21 ± 0.51 vs. 33.58% ± 0.44% CO 2 ; P < 0.025) significantly increased after 1 month, however sensitivity thresholds to thermal stimulation remained unchanged compared to baseline (P > 0.05). Prolonged use of 0.15% zinc-hyaluronate results in an improvement of tear film stability and a decrease of dry eye complaints. The decrease in corneal mechano-and polymodal receptor excitability suggests that zinc-hyaluronate helps to recover normal corneal sensitivity, and thus might have a beneficial additional effect on reducing ocular surface complaints in dry eye patients.

Management of patients with ocular manifestations in vesiculobullous disorders affecting the mouth.

PubMed

Hansen, M S; Klefter, O N; Julian, H O; Lynge Pedersen, A M; Heegaard, S

2017-10-01

Pemphigoid and pemphigus diseases as well as Stevens-Johnson syndrome present as vesiculobullous disorders of the skin and may additionally involve both the oral cavity and the ocular surface. Ocular involvement ranges from mild irritation and dry eye disease to chronic conjunctivitis, symblepharon, eyelid malposition, ocular surface scarring and severe visual loss. In addition to diagnostic assessments, ophthalmologists must treat the dry eye and meibomian gland dysfunction components of these diseases using a stepladder approach, including eyelid hygiene and lubricants. Topical anti-inflammatory therapy is used to treat acute inflammatory exacerbations of the ocular surface, but it cannot prevent scarring alone. Intralesional antimetabolite therapy can cause regression of conjunctival pathology in selected cases. Hence, patients with vesiculobullous disorders should be managed by a multidisciplinary team representing ophthalmology, dermatology, otolaryngology, oral medicine and pathology, internal medicine and intensive care. Systemic treatments including corticosteroids, azathioprine, cyclophosphamide, cyclosporine and mycophenolate mofetil help control inflammation. Intravenous immunoglobulins, plasmapheresis and targeted antibody therapy can be used in selected, severe and treatment-resistant cases. Local surgical management may include debridement of pseudomembranes, lysis of symblepharon, amniotic and mucous membrane grafting as well as reconstructive procedures. Prospective, multicentre, international studies are recommended to further support evidence-based practice. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Müller stem cell dependent retinal regeneration.

PubMed

Chohan, Annu; Singh, Usha; Kumar, Atul; Kaur, Jasbir

2017-01-01

Müller Stem cells to treat ocular diseases has triggered enthusiasm across all medical and scientific communities. Recent development in the field of stem cells has widened the prospects of applying cell based therapies to regenerate ocular tissues that have been irreversibly damaged by disease or injury. Ocular tissues such as the lens and the retina are now known to possess cell having remarkable regenerative abilities. Recent studies have shown that the Müller glia, a cell found in all vertebrate retinas, is the primary source of new neurons, and therefore are considered as the cellular basis for retinal regeneration in mammalian retinas. Here, we review the current status of retinal regeneration of the human eye by Müller stem cells. This review elucidates the current status of retinal regeneration by Müller stem cells, along with major retinal degenerative diseases where these stem cells play regenerative role in retinal repair and replacement. Copyright © 2016. Published by Elsevier B.V.

Oculoplastic technique of connecting a glaucoma valve shunt to extraorbital locations in cases of severe glaucoma.

PubMed

Rubin, Peter A D; Chang, Eli; Bernardino, Carlo Roberto; Hatton, Mark P; Dohlman, Claes H

2004-09-01

To describe a technique for inserting glaucoma shunts to the sinuses or the lacrimal sac as a means of lowering intraocular pressure in patients with refractory glaucoma associated with severe ocular surface disease. Nineteen patients with severe ocular surface disease necessitating a keratoprosthesis and with intractable glaucoma underwent placement of a modified Ahmed shunt to direct aqueous in the maxillary or ethmoid sinus or lacrimal sac. Intraocular pressure is presently well controlled without glaucoma medications in two thirds of patients. None of the patients had endophthalmitis. Established oculoplastic surgery techniques may be used to redirect aqueous to extraorbital locations and effectively lower intraocular pressure in patients with severe ocular surface disease and refractory glaucoma. This procedure has not been associated with endophthalmitis.

Recent developments on dry eye disease treatment compounds.

PubMed

Colligris, Basilio; Alkozi, Hanan Awad; Pintor, Jesus

2014-01-01

Dry eye syndrome is a common tears and ocular surface multifactorial disease, described by changes in the ocular surface epithelia related to reduced tears quantity and ocular surface sensitivity, leading to inflammatory reaction. Managing the eye inflammation proved helpful to patients with dry eye disease and current treatment is based on the use of topically applied artificial tear products/lubricants, tear retention management, stimulation of tear secretion and using anti-inflammatory drugs. In this article we revise the corresponding literature and patents assembling the new treatment approaches of novel and future pharmaceutical compounds destined for the dry eye disease treatment. The most frequent categories of compounds presented are secretagogues and anti-inflammatory drugs. These compounds are the research outcome of novel therapeutic strategies designed to reduce key inflammatory pathways and restore healthy tear film.

Use of fluid-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease

PubMed Central

Takahide, Kikuchi; Parker, Pablo M.; Wu, Michael; Hwang, William Y.K.; Carpenter, Paul A.; Moravec, Carina; Stehr, Barbara; Martin, Paul J.; Rosenthal, Perry; Forman, Stephen J.; Flowers, Mary E.D.

2007-01-01

Keratoconjunctivitis sicca (KCS) occurs in 40-60 % of patients with chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic cell transplantation. While immunosuppressive therapy is the primary treatment of chronic GVHD, ocular symptoms require measures to improve ocular lubrication, decrease inflammation and maintain mucosal integrity. The liquid corneal bandage provided by a fluid-ventilated, gas-permeable scleral lens (SL) has been effective in mitigating symptoms and resurfacing corneal erosions in patients with KCS related to causes other than chronic GVHD. We report outcomes in 9 consecutive patients referred for SL fitting for chronic GVHD-related severe KCS that was refractory to standard treatments. All patients reported improvement of ocular symptoms and reduced the use of topical lubricants after SL fitting resulting from decrease evaporation. No serious adverse events or infections attributable to the SL occurred. The median Ocular Surface Disease Index improved from 81 (75-100) to 21 (6-52) within 2 weeks after SL fitting and was 12 (2-53) at the time of last contact, 1-23 months (median, 8.0) after SL fitting. Disability related to KCS resolved in 7 patients after SL fitting. The use of SL appears to be safe and effective in patients with severe chronic GVHD-related KCS refractory to conventional therapies. PMID:17697963

Xeroderma pigmentosum with bilateral ocular surface squamous neoplasia and review of the literature

PubMed Central

Kalamkar, Charudutt; Radke, Nishant; Mukherjee, Amrita; Radke, Snehal

2016-01-01

Xeroderma pigmentosum is a rare genetic disorder associated with various ocular malignancies. Here we report a single paediatric case of xeroderma pigmentosum with bilateral ocular surface squamous neoplasia (OSSN) presenting with diffuse lesion in one eye and a large mass in the other eye. Diffuse OSSN in one eye was treated with topical chemotherapy using mitomycin-C (0.04%) and the large OSSN in the other eye was treated with a combination of surgery and topical chemotherapy. Long-term follow-up and a multimodality treatment approach are necessary to identify and manage recurrences of OSSN in XP. PMID:27166000

Periocular Reconstruction in Patients with Facial Paralysis.

PubMed

Joseph, Shannon S; Joseph, Andrew W; Douglas, Raymond S; Massry, Guy G

2016-04-01

Facial paralysis can result in serious ocular consequences. All patients with orbicularis oculi weakness in the setting of facial nerve injury should undergo a thorough ophthalmologic evaluation. The main goal of management in these patients is to protect the ocular surface and preserve visual function. Patients with expected recovery of facial nerve function may only require temporary and conservative measures to protect the ocular surface. Patients with prolonged or unlikely recovery of facial nerve function benefit from surgical rehabilitation of the periorbital complex. Current reconstructive procedures are most commonly intended to improve coverage of the eye but cannot restore blink. Copyright © 2016 Elsevier Inc. All rights reserved.

Xeroderma pigmentosum with bilateral ocular surface squamous neoplasia and review of the literature.

PubMed

Kalamkar, Charudutt; Radke, Nishant; Mukherjee, Amrita; Radke, Snehal

2016-05-10

Xeroderma pigmentosum is a rare genetic disorder associated with various ocular malignancies. Here we report a single paediatric case of xeroderma pigmentosum with bilateral ocular surface squamous neoplasia (OSSN) presenting with diffuse lesion in one eye and a large mass in the other eye. Diffuse OSSN in one eye was treated with topical chemotherapy using mitomycin-C (0.04%) and the large OSSN in the other eye was treated with a combination of surgery and topical chemotherapy. Long-term follow-up and a multimodality treatment approach are necessary to identify and manage recurrences of OSSN in XP. 2016 BMJ Publishing Group Ltd.

Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye.

PubMed

Wong, Aaron B C; Wang, Michael T M; Liu, Kevin; Prime, Zak J; Danesh-Meyer, Helen V; Craig, Jennifer P

2018-07-01

To assess tear film parameters, ocular surface characteristics, and dry eye symptomology in patients receiving topical anti-glaucoma medications. Thirty-three patients with a diagnosis of open angle glaucoma or ocular hypertension, receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross-sectional, investigator-masked, paired-eye comparison study. Tear film parameters, ocular surface characteristics, and dry eye symptomology of treated and fellow eyes were evaluated and compared. The mean ± SD age of the participants was 67 ± 12 years, and the mean ± SD treatment duration was 5.3 ± 4.4 years. Treated eyes had poorer non-invasive tear film breakup time (p = 0.03), tear film osmolarity (p = 0.04), bulbar conjunctival hyperaemia (p = 0.04), eyelid margin abnormality grade (p = 0.01), tear meniscus height (p = 0.03), and anaesthetised Schirmer value (p = 0.04) than fellow eyes. There were no significant differences in dry eye symptomology, meibomian gland assessments, and ocular surface staining between treated and fellow eyes (all p > 0.05). Adverse changes in tear film stability, tear osmolarity, conjunctival hyperaemia, and eyelid margins were observed in treated eyes. This suggests that inflammatory mechanisms may be implicated in the development of dry eye in patients receiving long term topical anti-glaucoma therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Graft versus host disease: what should the oculoplastic surgeon know?

PubMed

Tung, Cynthia I

2017-09-01

To provide a concise review of the oculoplastic manifestations of ocular graft versus host disease (GVHD), and to discuss their management. Ocular GVHD occurs as a common immune-mediated complication of hematopoietic stem cell transplantation that presents as a Stevens-Johnson-like syndrome in the acute phase or a Sjögren-like syndrome in the chronic phase. Cicatricial conjunctivitis may be underreported in ocular GVHD. The spectrum of oculoplastic manifestations includes GVHD of the skin, cicatricial entropion, nasolacrimal duct obstruction, and lacrimal gland dysfunction. Surgical treatment is indicated for patients with significant corneal complications from entropion. Surgical approach to repair of nasolacrimal duct obstruction is presented in this review, including modified approaches for treating patients at risk for keratitis sicca. Management of the ocular graft versus host patient may require a multidisciplinary approach involving collaboration from the oculoplastic surgeon, the corneal specialist, and the stem cell transplant physician. Oculoplastic manifestations of ocular GVHD typically present as cicatricial changes in the eyelid and lacrimal system. Careful oculoplastic and corneal evaluation are necessary when considering surgical management for the ocular GVHD patient.

Development of the EpiOcular(TM) eye irritation test for hazard identification and labelling of eye irritating chemicals in response to the requirements of the EU cosmetics directive and REACH legislation.

PubMed

Kaluzhny, Yulia; Kandárová, Helena; Hayden, Patrick; Kubilus, Joseph; d'Argembeau-Thornton, Laurence; Klausner, Mitchell

2011-09-01

The recently implemented 7th Amendment to the EU Cosmetics Directive and the EU REACH legislation have heightened the need for in vitro ocular test methods. To address this need, the EpiOcular(TM) eye irritation test (EpiOcular-EIT), which utilises the normal (non-transformed) human cell-based EpiOcular tissue model, has been developed. The EpiOcular-EIT prediction model is based on an initial training set of 39 liquid and 21 solid test substances and uses a single exposure period and a single cut-off in tissue viability, as determined by the MTT assay. A chemical is classified as an irritant (GHS Category 1 or 2), if the tissue viability is ≤ 60%, and as a non-irritant (GHS unclassified), if the viability is > 60%. EpiOcular-EIT results for the training set, along with results for an additional 52 substances, which included a range of alcohols, hydrocarbons, amines, esters, and ketones, discriminated between ocular irritants and non-irritants with 98.1% sensitivity, 72.9% specificity, and 84.8% accuracy. To ensure the long-term commercial viability of the assay, EpiOcular tissues produced by using three alternative cell culture inserts were evaluated in the EpiOcular-EIT with 94 chemicals. The assay results obtained with the initial insert and the three alternative inserts were very similar, as judged by correlation coefficients (r²) that ranged from 0.82 to 0.96. The EpiOcular-EIT was pre-validated in 2007/2008, and is currently involved in a formal, multi-laboratory validation study sponsored by the European Cosmetics Association (COLIPA) under the auspices of the European Centre for the Validation of Alternative Methods (ECVAM). The EpiOcular-EIT, together with EpiOcular's long history of reproducibility and proven utility for ultra-mildness testing, make EpiOcular a useful model for addressing current legislation related to animal use in the testing of potential ocular irritants. 2011 FRAME.

Application of Hydrogel Template Strategy in Ocular Drug Delivery.

PubMed

Shin, Crystal S; Marcano, Daniela C; Park, Kinam; Acharya, Ghanashyam

2017-01-01

The hydrogel template strategy was previously developed to fabricate homogeneous polymeric microparticles. Here, we demonstrate the versatility of the hydrogel template strategy for the development of nanowafer-based ocular drug delivery systems. We describe the fabrication of dexamethasone-loaded nanowafers using polyvinyl alcohol and the instillation of a nanowafer on a mouse eye. The nanowafer, a small circular disk, is placed on the ocular surface, and it releases a drug as it slowly dissolves over time, thus increasing ocular bioavailability and enhancing efficiency to treat eye injuries.

Evaluation of the Tear Function Tests and the Ocular Surface in First-Time Users of Silicone Hydrogel Contact Lenses.

PubMed

Yildiz Tasci, Yelda; Gürdal, Canan; Sarac, Ozge; Onusever, Aykut

2017-07-01

To evaluate the effects of three different silicone hydrogel contact lenses (SHCL), (balafilcon A, senofilcon A, and comfilcon A) on tear function tests, corneal thickness, and ocular surface cytology in first time contact lens users. In this prospective study, 120 eyes of 60 subjects were evaluated. Balafilcon A users were designated as group 1, senofilcon A users as group 2, and comfilcon A users as group 3. In all cases, before and after 6 months of contact lens wear, ocular surface disease index score (OSDI), tear breakup time (TBUT), Schirmer 1 test, central corneal thickness (CCT), central corneal epithelium thickness (CCET), and conjunctival impression cytology samples were evaluated. In group 1, 40 eyes of the 20 patients, in group 2, 40 eyes of the 20 patients, and in group 3, 40 eyes of the 20 patients were evaluated. The mean OSDI scores did not differ between the three groups after contact lens wear (p > 0.05). In group 1 and group 2, significant decrease was found in the mean TBUT 6 months after contact lens wear (p = 0.04, p < 0.001, respectively). In group 3, after 6 months of contact lens wear, the mean Schirmer 1 tear test was decreased significantly (p = 0.021). In all 3 groups, no significant change was observed in the mean CCT and CCET after contact lens wear (p > 0.05). After 6 months, the morphological changes in temporal and superior conjunctival epithelial cells were found to be significant in all groups (p < 0.001). Six months after SHCL wear, marked morphological changes occurred in the conjunctival epithelium. Tear function tests were also affected, while corneal thickness did not show any significant difference.

Efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye: a systematic review of randomized clinical trials.

PubMed

Wu, Di; Chen, Wang Qi; Li, Ryan; Wang, Yan

2015-06-01

To evaluate the efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye. Randomized clinical trials (RCTs) from MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were identified to evaluate the efficacy and safety of topical administration of diquafosol to patients with dry eyes. Data evaluation was based on endpoints including Schirmer test, tear film break-up time, ocular surface staining score, subjective symptom score, and adverse events. A total of 8 RCTs involving 1516 patients were selected based on the prespecified criteria. Significant improvement of Schirmer test values and tear film break-up time were reported in 40% (2 of 5) and 80% (4 of 5) studies, respectively. Ocular surface staining scores significantly decreased in 100% (fluorescein corneal staining, 6 of 6; Rose Bengal corneal and conjunctival staining, 4 of 4) RCTs. Symptoms significantly improved in 75% (6 of 8) RCTs in patients with dry eyes. No severe adverse events were reported with the concentration of diquafosol from 0.5% to 5%. Heterogeneity in study design prevented meta-analysis from statistical integration and summarization. Topical diquafosol seems to be a safe therapeutic option for the treatment of dry eye. The high variability of the selected RCTs compromised the strength of evidence and limits the determination of efficacy. However, the topical administration of diquafosol seems to be beneficial in improving the integrity of the epithelial cell layer of the ocular surface and mucin secretion in patients with dry eyes. This review indicates a need for standardized criteria and methods for evaluation to assess the efficacy of diquafosol in the future clinical trials.

Early Changes in Ocular Surface and Tear Inflammatory Mediators after Small-Incision Lenticule Extraction and Femtosecond Laser-Assisted Laser In Situ Keratomileusis

PubMed Central

Gao, Shaohui; Li, Saiqun; Liu, Liangping; Wang, Yong; Ding, Hui; Li, Lili; Zhong, Xingwu

2014-01-01

Purpose To characterize the early ocular-surface changes or tear inflammatory-mediators levels following small-incision lenticule extraction (ReLEx smile) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK). Methods Forty-seven myopic subjects were recruited for this prospective study. Fifteen underwent ReLEx smile and thirty-two underwent FS-LASIK. Corneal fluorescein (FL) staining, tear break-up time (TBUT), Schirmer I test (SIT), ocular surface disease index (OSDI) and central corneal sensitivity were evaluated in all participants. Tears were collected and analyzed for interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nerve growth factor (NGF) and intercellular adhesion molecule-1 (ICAM-1) levels using multiplex magnetic beads. All measurements were preformed preoperatively and 1 day, 1 week, 1 month and 3 months postoperatively. Results FL scores in ReLEx smile group were lower than those of FS-LASIK group 1 week postoperatively (P = 0.010). Compared to the FS-LASIK group, longer TBUT were observed in ReLEx smile group 1 month (P = 0.029) and 3 months (P = 0.045) postoperatively. No significant differences were found in tear secretion for the two groups (P>0.05). OSDI scores were higher in FS-LASIK group 1 month after surgery (P = 0.020). Higher central corneal sensitivity was observed in ReLEx smile group 1 week, 1 month and 3 months (P<0.05) postoperatively. Compared to FS-LASIK group, lower and faster recovery of IL-6 and NGF levels in tears was observed in ReLEx smile group postoperatively (P<0.05). Tears TNF-α and ICAM-1 concentrations were not significantly different between the two groups at any follow-up time (P>0.05). Moreover, IL-6 and NGF levels correlated with ocular surface changes after ReLEx smile or FS-LASIK. Conclusions In the early postoperative period, ReLEx smile results in milder ocular surface changes than FS-LASIK. Furthermore, the tear inflammatory mediators IL-6 and NGF may play a crucial role in the ocular surface healing process following ReLEx smile and FS-LASIK. PMID:25211490

Early changes in ocular surface and tear inflammatory mediators after small-incision lenticule extraction and femtosecond laser-assisted laser in situ keratomileusis.

PubMed

Gao, Shaohui; Li, Saiqun; Liu, Liangping; Wang, Yong; Ding, Hui; Li, Lili; Zhong, Xingwu

2014-01-01

To characterize the early ocular-surface changes or tear inflammatory-mediators levels following small-incision lenticule extraction (ReLEx smile) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK). Forty-seven myopic subjects were recruited for this prospective study. Fifteen underwent ReLEx smile and thirty-two underwent FS-LASIK. Corneal fluorescein (FL) staining, tear break-up time (TBUT), Schirmer I test (SIT), ocular surface disease index (OSDI) and central corneal sensitivity were evaluated in all participants. Tears were collected and analyzed for interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nerve growth factor (NGF) and intercellular adhesion molecule-1 (ICAM-1) levels using multiplex magnetic beads. All measurements were preformed preoperatively and 1 day, 1 week, 1 month and 3 months postoperatively. FL scores in ReLEx smile group were lower than those of FS-LASIK group 1 week postoperatively (P = 0.010). Compared to the FS-LASIK group, longer TBUT were observed in ReLEx smile group 1 month (P = 0.029) and 3 months (P = 0.045) postoperatively. No significant differences were found in tear secretion for the two groups (P>0.05). OSDI scores were higher in FS-LASIK group 1 month after surgery (P = 0.020). Higher central corneal sensitivity was observed in ReLEx smile group 1 week, 1 month and 3 months (P<0.05) postoperatively. Compared to FS-LASIK group, lower and faster recovery of IL-6 and NGF levels in tears was observed in ReLEx smile group postoperatively (P<0.05). Tears TNF-α and ICAM-1 concentrations were not significantly different between the two groups at any follow-up time (P>0.05). Moreover, IL-6 and NGF levels correlated with ocular surface changes after ReLEx smile or FS-LASIK. In the early postoperative period, ReLEx smile results in milder ocular surface changes than FS-LASIK. Furthermore, the tear inflammatory mediators IL-6 and NGF may play a crucial role in the ocular surface healing process following ReLEx smile and FS-LASIK.

Computer vision syndrome: a review.

PubMed

Blehm, Clayton; Vishnu, Seema; Khattak, Ashbala; Mitra, Shrabanee; Yee, Richard W

2005-01-01

As computers become part of our everyday life, more and more people are experiencing a variety of ocular symptoms related to computer use. These include eyestrain, tired eyes, irritation, redness, blurred vision, and double vision, collectively referred to as computer vision syndrome. This article describes both the characteristics and treatment modalities that are available at this time. Computer vision syndrome symptoms may be the cause of ocular (ocular-surface abnormalities or accommodative spasms) and/or extraocular (ergonomic) etiologies. However, the major contributor to computer vision syndrome symptoms by far appears to be dry eye. The visual effects of various display characteristics such as lighting, glare, display quality, refresh rates, and radiation are also discussed. Treatment requires a multidirectional approach combining ocular therapy with adjustment of the workstation. Proper lighting, anti-glare filters, ergonomic positioning of computer monitor and regular work breaks may help improve visual comfort. Lubricating eye drops and special computer glasses help relieve ocular surface-related symptoms. More work needs to be done to specifically define the processes that cause computer vision syndrome and to develop and improve effective treatments that successfully address these causes.

Impact of oral vitamin D supplementation on the ocular surface in people with dry eye and/or low serum vitamin D.

PubMed

Yang, Chih-Huang; Albietz, Julie; Harkin, Damien G; Kimlin, Michael G; Schmid, Katrina L

2018-02-01

To determine the possible association between serum vitamin D levels and dry eye symptoms, and the impact of an oral vitamin D supplement. Three linked studies were performed. (i) 29 older adult participants, (ii) 29 dry eyed participants, and (iii) 2-month vitamin D supplementation for 32 dry eyed/low serum vitamin D levelled participants. All participants were assessed by the Ocular Surface Diseases Index (OSDI) to determine dry eye symptoms, and the phenol red thread test (PRT) and/or Schirmer's tear test, tear meniscus height, non-invasive tear break up time, grading ocular surface redness and fluorescein staining of the cornea to detect the tear quality and ocular surface conditions. Blood samples were collected for serum vitamin D analysis and interleukin-6 (IL-6) levels. Among older adult participants, vitamin D levels were negatively correlated with dry eye symptoms, the severity of dry eye, and associated with tired eye symptom. Vitamin D levels of people with dry eye diagnosis were not correlated with OSDI scores and IL-6 levels; while IL-6 levels showed correlation with tear production. In supplement study, vitamin D levels increased by 29mol/l, while dry eye symptoms and grading of corneal staining appeared significant reductions. No significant changes in IL-6 levels. Low vitamin D levels (<50nmol/l) were associated with dry eye symptoms in older individuals but not those diagnosed with dry eye. Vitamin D supplement increased the vitamin D levels, and improved dry eye symptoms, the tear quality and ocular surface conditions. Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

[Oral flaxseed oil (Linum usitatissimum) in the treatment for dry-eye Sjögren's syndrome patients].

PubMed

Pinheiro, Manuel Neuzimar; dos Santos, Procópio Miguel; dos Santos, Regina Cândido Ribeiro; Barros, Jeison de Nadai; Passos, Luiz Fernando; Cardoso Neto, José

2007-01-01

To evaluate if oral flaxseed oil (Linum usitatissimum), which reduces the inflammation in rheumatoid arthritis, may help keratoconjunctivitis sicca's treatment in Sjögren's syndrome patients. In a randomized clinical trial, 38 female patients with rheumatoid arthritis or systemic lupus erithematosus associated with keratoconjunctivitis sicca and Sjögren's syndrome were consecutively selected from patients of the Department of Rheumatology of the Amazonas University Hospital. Keratoconjunctivitis sicca diagnosis was based on a dry-eye symptom survey score (Ocular Surface Disease Index - OSDI), Schirmer-I test, fluorescein break-up time, 1% Rose Bengal staining of ocular surface measured by the van Bijsterveld scale. All patients had ocular surface inflammation evaluated and quantified by conjunctival impression cytology, before and after the study. The subjects were divided into three groups with 13 (Group I), 12 (Group II) and 13 (Group III) patients. Group I received flaxseed oil capsules with a final 1 g/day dosis, Group II flaxseed oil capsules with a final 2 g/day dosis and Group III - controls - placebo, for 180 days. Comparing the results at the beginning and at the end of the treatment, statistically significant changes (p<0.05) in symptoms (OSDI), ocular surface inflammation quantified by conjunctival impression cytology, Schirmer-I test and fluorescein break-up time occurred in Groups I e II when compared to controls. Therapy with oral flaxseed oil capsules 1 or 2 g/day reduces ocular surface inflammation and ameliorates the symptoms of keratoconjunctivitis sicca in Sjögren's syndrome patients. Long-term studies are needed to confirm the role of this therapy for keratoconjunctivitis sicca in Sjögren's syndrome.

Corneal and conjunctival sensory function: the impact on ocular surface sensitivity of change from low to high oxygen transmissibility contact lenses.

PubMed

Golebiowski, Blanka; Papas, Eric B; Stapleton, Fiona

2012-03-09

Deprivation of oxygen to the ocular surface during contact lens wear has been implicated in the alteration of sensory function. This study investigates whether increasing oxygen availability through discontinuation of contact lens wear or transfer into highly oxygen transmissible (high Dk/t) lenses leads to a change in corneal or conjunctival sensitivity. Twenty-seven long-term extended wearers of low Dk/t soft contact lenses ceased lens wear for 1 week and were refitted with high Dk/t silicone hydrogel lenses. A control group of 25 nonwearers matched for age and sex was also recruited. Central corneal and inferior conjunctival sensitivity were measured using an air-jet aesthesiometer. Threshold was determined using a staircase technique. Measurements were taken during low Dk/t lens wear; after 1 week of no wear; and after 1, 3, 6, and 12 months of high Dk/t lens wear. Measurements were carried out on one occasion on the nonwearers. Corneal sensitivity decreased 1 week after discontinuation of low Dk/t lenses and no further change in sensitivity occurred with high Dk/t lens wear. Conjunctival sensitivity did not change over the same time frame. Ocular surface sensitivity in long-term low Dk/t soft lens wearers was similar to that of nonwearers. Sensitivity was higher in females than males in the nonwearers, but not in the lens-wearing group. An interaction of sex on change in conjunctival threshold was found in the lens wearers. These findings indicate that factors other than oxygen availability alone determine sensitivity of the ocular surface. Silicone hydrogel contact lenses appear to have only a minor impact on ocular surface sensitivity in previous lens wearers.

Temperatures of the Ocular Surface, Lid, and Periorbital Regions of Sjögren's, Evaporative, and Aqueous-Deficient Dry Eyes Relative to Normals.

PubMed

Abreau, Kerstin; Callan, Christine; Kottaiyan, Ranjini; Zhang, Aizhong; Yoon, Geunyoung; Aquavella, James V; Zavislan, James; Hindman, Holly B

2016-01-01

To compare the temperatures of the ocular surface, eyelid, and periorbital skin in normal eyes with Sjögren's syndrome (SS) eyes, evaporative dry eyes (EDE), and aqueous deficient dry eyes (ADDE). 10 eyes were analyzed in each age-matched group (normal, SS, EDE, and ADDE). A noninvasive infrared thermal camera captured two-dimensional images in three regions of interest (ROI) in each of three areas: the ocular surface, the upper eyelid, and the periorbital skin within a controlled environmental chamber. Mean temperatures in each ROI were calculated from the videos. Ocular surface time-segmented cooling rates were calculated over a 5-s blink interval. Relative to normal eyes, dry eyes had lower initial central OSTs (SS -0.71°C, EDE -0.55°C, ADDE -0.95°C, KW P<.0001) and lower central upper lid temperatures (SS -0.24°C, ADDE -0.51°C, and EDE -0.54°C, KW P<.0001). ADDE eyes had the lowest initial central OST (P<.0001), while EDE eyes had the lowest central lid temperature and lower periorbital temperatures (P<.0001). Over the 5-s interblink interval, the greatest rate of temperature loss occurred following eyelid opening, but varied by group (normals -0.52, SS -0.73, EDE -0.63, and ADDE -0.75°C/s). The ADDE group also had the most substantial heat loss over the 5-s interblink interval (-0.97°C). Differences in OST may be related to thermal differences in lids and periorbita along with an altered tear film. Thermography of the ocular surface, lids, and surrounding tissues may help to differentiate between different etiologies of dry eye. Copyright © 2016 Elsevier Inc. All rights reserved.

Conjunctiva-Associated Lymphoid Tissue (CALT) Reactions to Antiglaucoma Prostaglandins with or without BAK-Preservative in Rabbit Acute Toxicity Study

PubMed Central

Liang, Hong; Baudouin, Christophe; Labbe, Antoine; Riancho, Luisa; Brignole-Baudouin, Françoise

2012-01-01

Conjunctiva-associated lymphoid tissue (CALT) is closely associated with ocular surface immunity. This study investigated the effects of antiglaucoma prostaglandin analogs with or without benzalkonium chloride (BAK) preservative on organized CALT using an acute toxic model. A total of 48 albino rabbits were used and seven groups of treatments were constituted. Solutions (50 µl) of PBS, 0.02%BAK, 0.02%BAK+latanoprost, 0.015%BAK+travoprost, 0.005%BAK+bimatoprost, BAK-freetravoprost preserved with the SofZia® system or BAK-freetafluprost were instilled 15 times at 5-min intervals in both eyes. CALT changes were analyzed using in vivo confocal microscopy (IVCM), immunohistology in cryosections for detecting MUC-5AC+ mucocytes and CD45+ hematopoietic cells. Antiglaucoma eye drops stimulated inflammatory cell infiltration in the CALT, and seemed to be primarily related to the concentration of their BAK content. The CALT reaction after instillation of BAK-containing eye drops was characterized by inflammatory cell infiltration in the dome and intrafollicular layers and by cell circulation inside the lymph vessels. CD45 was strongly expressed in the CALT after instillation of all BAK-containing solutions at 4 h and decreased at 24 h. The number of MUC-5AC+ mucocytes around the CALT structure decreased dramatically after instillation of BAK-containing solutions. This study showed for the first time the in vivo aspect of rabbit CALT after toxic stimuli, confirming the concentration-dependent toxic effects of BAK. IVCM-CALT analysis could be a pertinent tool in the future for understanding the immunotoxicologic challenges in the ocular surface and would provide useful criteria for evaluating newly developed eye drops. PMID:22442734

Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation.

PubMed

Anitua, Eduardo; Sanchez, Mikel; Merayo-Lloves, Jesus; De la Fuente, Maria; Muruzabal, Francisco; Orive, Gorka

2011-08-01

Plasma rich in growth factors (PRGF-Endoret) technology is an autologous platelet-enriched plasma obtained from patient's own blood, which after activation with calcium chloride allows the release of a pool of biologically active proteins that influence and promote a range of biological processes including cell recruitment, and growth and differentiation. Because ocular surface wound healing is mediated by different growth factors, we decided to explore the potential of PRGF-Endoret technology in stimulating the biological processes related with fibroblast-induced tissue repair. Furthermore, the anti-fibrotic properties of this technology were also studied. Blood from healthy donors was collected, centrifuged and, whole plasma column (WP) and the plasma fraction with the highest platelet concentration (F3) were drawn off, avoiding the buffy coat. Primary human cells including keratocytes and conjunctival fibroblasts were used to perform the "in vitro" investigations. The potential of PRGF-Endoret in promoting wound healing was evaluated by means of a proliferation and migration assays. Fibroblast cells were induced to myofibroblast differentiation after the treatment with 2.5 ng/mL of TGF-β1. The capability of WP and F3 to prevent and inhibit TGF-β1-induced differentiation was evaluated. Results show that this autologous approach significantly enhances proliferation and migration of both keratocytes and conjunctival fibroblasts. In addition, plasma rich in growth factors prevents and inhibits TGF-β1-induced myofibroblast differentiation. No differences were found between WP and F3 plasma fractions. These results suggest that PRGF-Endoret could reduce scarring while stimulating wound healing in ocular surface. F3 or whole plasma column show similar biological effects in keratocytes and conjunctival fibroblast cells.

Effects of the Loss of Conjunctival Muc16 on Corneal Epithelium and Stroma in Mice

PubMed Central

Shirai, Kumi; Okada, Yuka; Cheon, Dong-Joo; Miyajima, Masayasu; Behringer, Richard R.; Yamanaka, Osamu; Saika, Shizuya

2014-01-01

Purpose. To examine the role of conjunctival Muc16 in the homeostasis of the ocular surface epithelium and stroma using Muc16-null knockout (KO) mice. Methods. We used KO mice (n = 58) and C57/BL6 (WT) mice (n = 58). Histology and immunohistochemistry were employed to analyze the phenotypes in the ocular surface epithelium. The expression of phospho-Stat3, AP-1 components, interleukin 6 (IL-6), and tumor necrosis factor-α (TNFα) in the cornea and conjunctiva was examined. The shape of the nuclei of corneal epithelial cells was examined to evaluate intraepithelial cell differentiation. Epithelial cell proliferation was studied using bromo-deoxyuridine labeling. Finally, the wound healing of a round defect (2-mm diameter) in the corneal epithelium was measured. The keratocyte phenotype and macrophage invasion in the stroma were evaluated after epithelial repair. Results. The loss of Muc16 activated Stat3 signal, affected JunB signal, and upregulated the expression of IL-6 in the conjunctiva. Basal-like cells were observed in the suprabasal layer of the corneal epithelium with an increase in proliferation. The loss of Muc16 accelerated the wound healing of the corneal epithelium. The incidence of myofibroblast appearance and macrophage invasion were more marked in KO stroma than in WT stroma after epithelial repair. Conclusions. The loss of Muc16 in the conjunctiva affected the homeostasis of the corneal epithelium and stroma. The mechanism might include the upregulation of the inflammatory signaling cascade (i.e., Stat3 signal, and IL-6 expression in the KO conjunctiva). Current data provides insight into the research of the pathophysiology of dry eye syndrome. PMID:24812549

Recent developments on dry eye disease treatment compounds

PubMed Central

Colligris, Basilio; Alkozi, Hanan Awad; Pintor, Jesus

2013-01-01

Dry eye syndrome is a common tears and ocular surface multifactorial disease, described by changes in the ocular surface epithelia related to reduced tears quantity and ocular surface sensitivity, leading to inflammatory reaction. Managing the eye inflammation proved helpful to patients with dry eye disease and current treatment is based on the use of topically applied artificial tear products/lubricants, tear retention management, stimulation of tear secretion and using anti-inflammatory drugs. In this article we revise the corresponding literature and patents assembling the new treatment approaches of novel and future pharmaceutical compounds destined for the dry eye disease treatment. The most frequent categories of compounds presented are secretagogues and anti-inflammatory drugs. These compounds are the research outcome of novel therapeutic strategies designed to reduce key inflammatory pathways and restore healthy tear film. PMID:24526854

Dry eyes: etiology and management.

PubMed

Latkany, Robert

2008-07-01

Until recently, the cause of dry eye syndrome was uncertain and the treatment was palliative. Since discovering that dry eyes are caused by inflammation, there has been an abundance of research focusing on anti-inflammatory therapies, other contributing causes, and better diagnostic testing. This review summarizes some of the interesting published research on ocular surface disease over the past year. The definition of dry eye now highlights the omnipresent symptom of blurry vision. The re-evaluation of ocular surface staining, tear meniscus height, and visual change will allow for a better diagnosis and understanding of dry eyes. Punctal plugs, and oral and topical anti-inflammatory use will strengthen our arsenal against ocular surface disease. Major progress has occurred in the past few years in gaining a better understanding of the etiology of dry eye syndrome, which will inevitably lead to more effective therapeutic options.

Ocular melanoma metastatic to skin: the value of HMB-45 staining.

PubMed

Schwartz, Robert A; Kist, Joseph M; Thomas, Isabelle; Fernández, Geover; Cruz, Manuel A; Koziorynska, Ewa I; Lambert, W Clark

2004-06-01

Cutaneous metastatic disease is an important finding that may represent the first sign of systemic cancer, or, if already known, that may change tumor staging and thus dramatically altered therapeutic plans. Although cutaneous metastases are relatively frequent in patients with cutaneous melanoma, they are less so from ocular melanoma. To demonstrate the value of HMB-45, staining in the detection of ocular melanoma metastatic to skin. The immunohistochemical stain HMB-45 a monoclonal antibody directed against intact human melanoma cells, was employed on a skin biopsy specimen from a cutaneous tumor. HMB-45 staining was positive in the atypical hyperchromatic cells of the deep dermis. HMB-45 may be of value in the detection of ocular melanoma metastatic to skin. Cutaneous metastatic disease is a somewhat common and extremely important diagnosis. Although cutaneous metastases from cutaneous melanoma are relatively frequent, those from ocular melanomas are less so. Use of histochemical staining, especially the HMB-45 stain, allows confirmation of the diagnosis.

Ocular sarcoidosis: new diagnostic modalities and treatment.

PubMed

Yang, Sung J; Salek, Sherveen; Rosenbaum, James T

2017-09-01

Ocular involvement in sarcoidosis is present in up to 80% of patients and is frequently manifested before diagnosis of the underlying systemic disease. Considering the therapeutic consequences, early diagnosis of the underlying disease is advantageous in patients presenting with ocular inflammation. There are several ocular findings suggestive of underlying sarcoidosis, such as granulomatous keratic precipitates, iris nodules, cells in the vitreous humor known as snowballs and snowbanks, and retinal periphlebitis. High suspicion is crucial for the diagnosis of sarcoidosis. This review on ocular sarcoidosis will mainly focus on new diagnostic and treatment modalities. Recent studies found possible new diagnostic indicators for the diagnosis of ocular sarcoidosis which include not only serum profiles but also vitreous sample analysis. Ophthalmologic imaging techniques have improved to investigate the ocular structure in detail. Results from recent uveitis clinical trials have included sarcoidosis as an underlying cause and have reported positive results. The diagnosis of ocular sarcoidosis can be challenging in some cases. High suspicion is important to diagnose ocular sarcoidosis with various laboratory and ophthalmic tools. There are many possible options for the treatment of ocular sarcoidosis including various biologic agents.

Dry eye disease caused by viral infection: review.

PubMed

Alves, Monica; Angerami, Rodrigo Nogueira; Rocha, Eduardo Melani

2013-01-01

Dry eye disease and ocular surface disorders may be caused or worsened by viral agents. There are several known and suspected virus associated to ocular surface diseases. The possible pathogenic mechanisms for virus-related dry eye disease are presented herein. This review serves to reinforce the importance of ophthalmologists as one of the healthcare professional able to diagnose a potentially large number of infected patients with high prevalent viral agents.

Relevance of Lipid-Based Products in the Management of Dry Eye Disease

PubMed Central

Amrane, Mourad; Faure, Marie-Odile; Holopainen, Juha M.; Tong, Louis

2017-01-01

Abstract Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air–water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed. PMID:28956698

Contributions of ocular surface components to matrix-metalloproteinases (MMP)-2 and MMP-9 in feline tears following corneal epithelial wounding.

PubMed

Petznick, Andrea; Madigan, Michele C; Garrett, Qian; Sweeney, Deborah F; Evans, Margaret D M

2013-01-01

This study investigated ocular surface components that contribute to matrix-metalloproteinase (MMP)-2 and MMP-9 found in tears following corneal epithelial wounding. Laboratory short-haired cats underwent corneal epithelial debridement in one randomly chosen eye (n = 18). Eye-flush tears were collected at baseline and during various healing stages. Procedural control eyes (identical experimental protocol as wounded eyes except for wounding, n = 5) served as controls for tear analysis. MMP activity was analyzed in tears using gelatin zymography. MMP staining patterns were evaluated in ocular tissues using immunohistochemistry and used to determine MMP expression sites responsible for tear-derived MMPs. The proMMP-2 and proMMP-9 activity in tears was highest in wounded and procedural control eyes during epithelial migration (8 to 36 hours post-wounding). Wounded eyes showed significantly higher proMMP-9 in tears only during and after epithelial restratification (day 3 to 4 and day 7 to 28 post-wounding, respectively) as compared to procedural controls (p<0.05). Tears from wounded and procedural control eyes showed no statistical differences for pro-MMP-2 and MMP-9 (p>0.05). Immunohistochemistry showed increased MMP-2 and MMP-9 expression in the cornea during epithelial migration and wound closure. The conjunctival epithelium exhibited highest levels of both MMPs during wound closure, while MMP-9 expression was reduced in conjunctival goblet cells during corneal epithelial migration followed by complete absence of the cells during wound closure. The immunostaining for both MMPs was elevated in the lacrimal gland during corneal healing, with little/no change in the meibomian glands. Conjunctival-associated lymphoid tissue (CALT) showed weak MMP-2 and intense MMP-9 staining. Following wounding, migrating corneal epithelium contributed little to the observed MMP levels in tears. The major sources assessed in the present study for tear-derived MMP-2 and MMP-9 following corneal wounding are the lacrimal gland and CALT. Other sources included stromal keratocytes and conjunctiva with goblet cells.

Investigational and experimental drugs for intraocular pressure reduction in ocular hypertension and glaucoma.

PubMed

Lusthaus, Jed Asher; Goldberg, Ivan

2016-10-01

Intraocular pressure (IOP) is the most significant modifiable risk factor to prevent onset or progression of glaucoma. Glaucoma prevalence continues to increase, emphasizing the need for improved ocular hypotensive treatment options. To try to improve on both tolerance and IOP control of currently available therapies, different receptors or mechanisms are being explored to reduce IOP more effectively and to improve tolerance. We review synthetic topical and oral drugs in early development for the management of ocular hypertension and glaucoma. New therapeutic agents for IOP control have been discovered; some appear to be reasonably tolerated. IOP reduction may be limited with some agents, but other benefits although unproven may compensate for this, such as less ocular surface disease, enhanced neuro-protection or increased ocular blood flow. Further product development promises improved treatment options for ocular hypertensives and glaucoma sufferers.

Ocular surface disease in patients with glaucoma or ocular hypertension treated with either BAK-preserved latanoprost or BAK-free travoprost

PubMed Central

Katz, Gregory; Springs, Clark L; Craven, E Randy; Montecchi-Palmer, Michela

2010-01-01

Purpose The preservative benzalkonium chloride (BAK) may adversely affect ocular surface health. This study evaluated symptoms of ocular surface disease (OSD) in patients previously treated with a BAK-preserved therapy to lower their intraocular pressure, who either continued that therapy or switched to a BAK-free therapy. Methods Eligible adult patients with ocular hypertension or open-angle glaucoma that had been controlled with BAK-preserved latanoprost 0.005% monotherapy (Xalatan®) for at least one month and had a score of ≥ 13 (0 = none, 100 = most severe) on the Ocular Surface Disease Index (OSDI) questionnaire were entered into this prospective, double-masked, randomized, active-controlled, multicenter trial. By random assignment, patients either continued with BAK-preserved latanoprost 0.005% or transitioned to BAK-free travoprost 0.004% (Travatan Z® ophthalmic solution). OSDI scores were assessed again after six and 12 weeks. Results For the 678 evaluable patients, mean change in OSDI score from baseline to week 12 favored the travoprost 0.004% BAK-free group, but was not statistically different between groups (P = 0.10). When patients with mild OSD at baseline were assessed after 12 weeks, the mean OSDI score was significantly lower (P = 0.04) in the BAK-free travoprost 0.004% group (score = 11.6 ± 10.8 units) than in the BAK-preserved latanoprost 0.005% group (score = 14.4 ± 11.9 units), and a significantly larger percentage (P < 0.01) improved to normal OSDI scores in the BAK-free travoprost 0.004% group (62.9% of group) than in the BAK-preserved latanoprost 0.005% group (47.0% of group). Patients pretreated with BAK-preserved latanoprost 0.005% for >24 months were significantly more likely (P = 0.03) to improve to a normal OSDI score after 12 weeks if they were switched to BAK-free travoprost 0.004% (47.9% of group) than if they remained on BAK-preserved latanoprost 0.005% (33.9% of group). Conclusions Switching from BAK-preserved latanoprost 0.005% to BAK-free travoprost 0.004% yielded significant improvements in symptoms of OSD in patients with glaucoma or ocular hypertension. PMID:21151330

Analysis of Factors Associated With the Tear Film Lipid Layer Thickness in Normal Eyes and Patients With Dry Eye Syndrome.

PubMed

Jung, Ji Won; Park, Si Yoon; Kim, Jin Sun; Kim, Eung Kweon; Seo, Kyoung Yul; Kim, Tae-Im

2016-08-01

To determine the effects of clinical variables, including age, sex, history of refractive or cataract surgery, contact lens use, and ocular surface and meibomian gland parameters on the lipid layer thickness (LLT) in normal subjects and patients with dry eye syndrome (DES). A total of 64 normal subjects and 326 patients with DES were enrolled, and they underwent measurements of LLT with a LipiView interferometer and tear meniscus height using optical coherence tomography, tear film break-up time (TBUT) determination, ocular surface staining, Schirmer's test, examination of the lid margins and meibomian glands, and assessment using the Ocular Surface Disease Index (OSDI). In normal subjects, the median (range) LLT was 67 (33-100) nm, and age was the only factor that was significantly associated with LLT (β = 0.678, P = 0.028). In patients with DES, the median (range) LLT was 84 (20-100) nm, and 79.0% of the participants fulfilled the diagnostic criteria for meibomian gland dysfunction (MGD). In a multivariate analysis, increased age and female sex were significantly related to increased LLT (β = 0.282, P = 0.005 and β = 11.493, P < 0.001), and hypersecretory MGD and lid margin inflammation were independently associated with increased LLT (β = 11.299, P = 0.001 and β = 12.747, P = 0.001). Lipid layer thickness measurements using a new interferometer are significantly affected by demographic factors such as age, sex, ocular surgical history, and MGD type. Therefore, all of these factors must be considered in the diagnosis of ocular surface diseases.

Ocular surface temperature in patients with evaporative and aqueous-deficient dry eyes: a thermographic approach.

PubMed

Matteoli, S; Favuzza, E; Mazzantini, L; Aragona, P; Cappelli, S; Corvi, A; Mencucci, R

2017-07-26

In recent decades infrared thermography (IRT) has facilitated accurate quantitative measurements of the ocular surface temperature (OST), applying a non-invasive procedure. The objective of this work was to develop a procedure based on IRT, which allows characterizing of the cooling of the ocular surface of patients suffering from dry eye syndrome, and distinguishing among patients suffering from aqueous deficient dry eye (ADDE) and evaporative dry eyes (EDE). All patients examined (34 females and 4 males, 23-84 years) were divided into two groups according to their Schirmer I result (⩽ 7 mm for ADDE and  >  7 mm for EDE), and the OST was recorded for 7 s at 30 Hz. For each acquisition, the temperatures of the central cornea (CC) as well as those of both temporal and nasal canthi were investigated. Findings showed that the maximum temperature variation (up to 0.75  ±  0.29 °C) was at the CC for both groups. Furthermore, patients suffering from EDE tended to have a higher initial OST than those with ADDE, explained by the greater quantity of the tear film, evenly distributed over the entire ocular surface, keeping the OST higher initially. Results also showed that EDE patients had an average cooling rate higher than those suffering from ADDE, confirming the excessive evaporation of the tear film. Ocular thermography paves the way to become an effective tool for differentiating between the two different etiologies of dry eye syndrome.

Ocular complications of diabetes mellitus

PubMed Central

Sayin, Nihat; Kara, Necip; Pekel, Gökhan

2015-01-01

Diabetes mellitus (DM) is a important health problem that induces ernestful complications and it causes significant morbidity owing to specific microvascular complications such as, retinopathy, nephropathy and neuropathy, and macrovascular complications such as, ischaemic heart disease, and peripheral vasculopathy. It can affect children, young people and adults and is becoming more common. Ocular complications associated with DM are progressive and rapidly becoming the world’s most significant cause of morbidity and are preventable with early detection and timely treatment. This review provides an overview of five main ocular complications associated with DM, diabetic retinopathy and papillopathy, cataract, glaucoma, and ocular surface diseases. PMID:25685281

The Role of Titanium Surface Microtopography on Adhesion, Proliferation, Transformation, and Matrix Deposition of Corneal Cells.

PubMed

Zhou, Chengxin; Lei, Fengyang; Chodosh, James; Paschalis, Eleftherios I

2016-04-01

Titanium (Ti) is an excellent implantable biomaterial that can be further enhanced by surface topography optimization. Despite numerous data from orthopedics and dentistry, the effect of Ti surface topography on ocular cells is still poorly understood. In light of the recent adaptation of Ti in the Boston Keratoprosthesis artificial cornea, we attempted to perform an extended evaluation of the effect of Ti surface topography on corneal cell adhesion, proliferation, cytotoxicity, transformation, and matrix deposition. Different surface topographies were generated on medical grade Ti-6Al-4V-ELI (extra-low interstitial), with linearly increased roughness (polished to grit blasted). Biological response was evaluated in vitro using human corneal limbal epithelial (HCLE) cells, stromal fibroblasts (HCF), and endothelial cells (HCEnC). None of the Ti surface topographies caused cytotoxicity to any of the three corneal cell types. However, rough Ti surface inhibited HCLE and HCF cell adhesion and proliferation, while HCEnC proliferation was unaffected. Long-term experiments with HCF revealed that rough Ti surface with R(a) (the arithmetic average of the profile height from the mean line) ≥ 1.15 μm suppressed HCF focal adhesion kinase phosphorylation, changed fibroblast morphology, and caused less aligned and reduced deposition of collagen matrix as compared to smooth Ti (R(a) ≤ 0.08 μm). In the presence of transforming growth factor β1 (TGFβ1) stimulation, rough Ti inhibited alpha-smooth muscle actin (α-SMA) expression and collagen deposition, leading to decreased myofibroblast transformation and disorganization of the collagen fibrils as compared to smooth Ti. This study suggests that Ti surface topography regulates corneal cell behavior in a tissue-dependent manner that varies across the corneal strata. Contrary to the accepted paradigm, smooth surface topography can enhance cell adhesion and proliferation and increase matrix deposition by corneal cells.

Evaluation of Ocular Surface Disease in Patients with Glaucoma

PubMed Central

Mathews, Priya M.; Ramulu, Pradeep Y.; Friedman, David S.; Utine, Canan A.; Akpek, Esen K.

2013-01-01

Purpose To evaluate the subjective and objective measures of ocular surface disease in patients with glaucoma. Design Cross-sectional study. Participants Sixty-four glaucoma subjects with bilateral visual field (VF) loss and 59 glaucoma suspects with normal VFs. Methods Consecutive patients were recruited prospectively from the Wilmer Eye Institute Glaucoma Clinic. Main Outcome Measures Tear film breakup time (TBUT), corneal staining score (0–15), and Schirmer’s test results were included as objective metrics, whereas the Ocular Surface Disease Index (OSDI) questionnaire was administered to assess symptoms. Total OSDI score, vision-related subscore (derived from questions about vision and task performance), and discomfort-related subscore (derived from questions about ocular surface discomfort) were calculated for each subject. Results Seventy-five percent (48/64) of glaucoma subjects and 41% (24/59) of glaucoma suspects were receiving topical medications. The corneal staining grade was greater in glaucoma subjects than in glaucoma suspects (6.4 vs. 4.1; P<0.001), but groups did not differ with regard to TBUT or Schirmer’s results (P>0.20 for both). Multivariate regression models showed that topical glaucoma therapy burden was associated with a significantly higher total corneal staining grade (β, +0.9 for each additional glaucoma drop; 95% confidence interval [CI], 0.5–1.3; P<0.001), but not with TBUT or Schirmer’s results (P>0.20 for both). Glaucoma subjects had significantly higher total OSDI scores than glaucoma suspects (16.7 vs. 7.9; P<0.001). This largely was the result of higher vision-related subscores in the glaucoma group (11.1 vs. 3.3; P<0.001). Ocular discomfort–related subscores, however, were similar in both groups (5.7 vs. 4.6; P = 0.30). In multivariate analyses, each 5-decibel decrement in better-eye VF mean deviation was associated with a 4.7-point increase in total OSDI score (95% CI, 1.9–7.5; P = 0.001) and a 3.7-point increase in the vision-related subscore (95% CI, 1.7–5.6; P<0.001) but did not predict a higher discomfort-related subscore (β, 1.1 point; P = 0.07). Topical glaucoma therapy burden was not associated with higher total OSDI score or vision- or discomfort-related subscore (P>0.20 for all). Conclusions Glaucoma is associated with significant ocular surface disease, and topical glaucoma therapy burden seems predictive of corneal staining severity. However, OSDI is a poor metric for capturing ocular surface disease in glaucoma because symptoms seem to be related largely to VF loss. PMID:23714318

Vision Integrating Strategies in Ophthalmology and Neurochemistry (VISION)

DTIC Science & Technology

2016-08-01

ocular hypertension ). We have developed techniques to quantify damage to the retina, optic nerve, and visual axis in the brain (i.e. superior...injury with different injury-initiating mechanisms (i.e. optic nerve crush, retinal ischemia/reperfusion, and chronic ocular hypertension ). We...protected retinal ganglion cells from ocular hypertension induced damage and appeared to stimulate axonal regeneration. Sigma-1 receptor agonists and

The potential of nanofibers in tissue engineering and stem cell therapy.

PubMed

Gholizadeh-Ghaleh Aziz, Shiva; Gholizadeh-Ghaleh Aziz, Sara; Akbarzadeh, Abolfazl

2016-08-01

Electrospinning is a technique in which materials in solution are shaped into continuous nano- and micro-sized fibers. Combining stem cells with biomaterial scaffolds and nanofibers affords a favorable approach for bone tissue engineering, stem cell growth and transfer, ocular surface reconstruction, and treatment of congenital corneal diseases. This review seeks to describe the current examples of the use of scaffolds in stem cell therapy. Stem cells are classified as adult or embryonic stem (ES) cells, and the advantages and drawbacks of each group are detailed. The nanofibers and scaffolds are further classified in Tables I and II , which describe specific examples from the literature. Finally, the current applications of biomaterial scaffolds containing stem cells for tissue engineering applications are presented. Overall, this review seeks to give an overview of the biomaterials available for use in combination with stem cells, and the application of nanofibers in stem cell therapy.

Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery.

PubMed

Xu, Tingting; Xu, Xiaoyue; Gu, Yan; Fang, Lei; Cao, Feng

2018-01-01

To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site. The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan-glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases. CG-GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC). CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects. The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site.

Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery

PubMed Central

Gu, Yan

2018-01-01

Background To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site. Purpose The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan-glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases. Materials and methods CG-GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC). Results CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects. Conclusions The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site. PMID:29491707

Microbial Keratitis: Could Contact Lens Material Affect Disease Pathogenesis?

PubMed Central

Evans, David J.; Fleiszig, Suzanne M. J.

2012-01-01

Microbial keratitis is a sight-threatening complication associated with contact lenses. The introduction of silicone hydrogel lens materials with increased oxygen transmission to the ocular surface has not significantly altered the incidence of microbial keratitis. These data suggest that alternate, or additional, predisposing factors involving lens wear must be addressed to reduce or eliminate these infections. The contact lens can provide a surface for microbial growth in situ, and can also influence ocular surface homeostasis through effects on the tear fluid and corneal epithelium. Thus, it is intuitive that future contact lens materials could make a significant contribution to preventing microbial keratitis. Design of the “right” material to prevent microbial keratitis requires understanding the effects of current materials on bacterial virulence in the cornea, and on ocular surface innate defenses. Current knowledge in each of these areas will be presented, with a discussion of future directions needed to understand the influence of lens material on the pathogenesis of microbial keratitis. PMID:23266587

In vitro effects of preserved and unpreserved anti-allergic drugs on human corneal epithelial cells.

PubMed

Guzman-Aranguez, Ana; Calvo, Patricia; Ropero, Inés; Pintor, Jesús

2014-11-01

Treatment with topical eye drops for long-standing ocular diseases like allergy can induce detrimental side effects. The purpose of this study was to investigate in vitro cytotoxicity of commercially preserved and unpreserved anti-allergic eye drops on the viability and barrier function of monolayer and stratified human corneal-limbal epithelial cells. Cells were treated with unpreserved ketotifen solution, benzalkonium chloride (BAC)-containing anti-allergic drugs (ketotifen, olopatadine, levocabastine) as well as BAC alone. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine cell viability. Effects of compounds on barrier function were analyzed measuring transepithelial electrical resistance (TEER) to determine paracellular permeability and rose bengal assays to evaluate transcellular barrier formation. The BAC-preserved anti-allergic formulations and BAC alone significantly reduced cell viability, monolayer cultures being more sensitive to damage by these solutions. Unpreserved ketotifen induced the least diminution in cell viability. The extent of decrease of cell viability was clearly dependent of BAC presence, but it was also affected by the different types of drugs when the concentration of BAC was low and the short time of exposure. Treatment with BAC-containing anti-allergic drugs and BAC alone resulted in increased paracellular permeability and loss of transcellular barrier function as indicated by TEER measurement and rose bengal assays. The presence of the preservative BAC in anti-allergic eye drop formulations contributes importantly to the cytotoxic effects induced by these compounds. Stratified cell cultures seem to be a more relevant model for toxicity evaluation induced on the ocular surface epithelia than monolayer cultures.

Regulatory requirements in the good manufacturing practice production of an epithelial cell graft for ocular surface reconstruction.

PubMed

Sheth-Shah, Radhika; Vernon, Amanda J; Seetharaman, Shankar; Neale, Michael H; Daniels, Julie T

2016-04-01

In the past decade, stem cell therapy has been increasingly employed for the treatment of various diseases. Subsequently, there has been a great interest in the manufacture of stem cells under good manufacturing practice, which is required by law for their use in humans. The cells for sight Stem Cell Therapy Research Unit, based at UCL Institute of Ophthalmology, delivers somatic cell-based and tissue-engineered therapies to patients suffering from blinding eye diseases at Moorfields Eye Hospital (London, UK). The following article is based on our experience in the conception, design, construction, validation and manufacturing within a good manufacturing practice manufacturing facility based in the UK. As such the regulations can be extrapolated to the 28 members stated within the EU. However, the principles may have a broad relevance outside the EU.

In vivo detection of clinically non-apparent ocular surface inflammation in patients with meibomian gland dysfunction-associated refractory dry eye symptoms: a pilot study

PubMed Central

Qazi, Y; Kheirkhah, A; Blackie, C; Cruzat, A; Trinidad, M; Williams, C; Korb, D R; Hamrah, P

2015-01-01

Purpose The utility of in vivo confocal microscopy (IVCM) in the investigation of palpebral conjunctival and corneal inflammation in patients with meibomian gland dysfunction (MGD)-associated refractory dry eye symptoms following gland expression, despite objective clinical improvement. Methods A retrospective, observational pilot study was conducted evaluating five patients with MGD-associated refractory dry eye symptoms and three control groups: symptomatic untreated MGD patients (n=3), treatment-responsive MGD patients with improved symptoms (n=3) and asymptomatic healthy normals (n=11). Ocular surface disease index (OSDI) scores, tear break-up time (TBUT), the number of meibomian glands yielding liquid secretion (MGYLS), palpebral conjunctival epithelial and substantia propria immune cell (EIC, SIC), and corneal dendritic cell (DC) densities were measured. Results Despite clinical improvement (TBUT: 6.4±1.2 s to 10.1±2.1 s, P=0.03; MGYLS: 3.5±0.8 glands to 7.0±1.1 glands, P=0.13) and a normal clinical examination post treatment, MGD patients remained symptomatic. IVCM revealed increased immune cells in the palpebral conjunctiva (refractory MGD EIC=592.6±110.1 cells/mm2; untreated MGD EIC=522.6±104.7 cells/mm2, P=0.69; responsive MGD EIC=194.9±119.4 cells/mm2, P<0.01; normals EIC=123.7±19.2 cells/mm2, P< 0.001), but not the cornea (refractory MGD DC=60.9±28.3 cells/mm2; normals DC=25.9±6.3 cells/mm2; P=0.43). EIC did not correlate with TBUT (Rs=−0.26, P=0.33). OSDI scores correlated with both EIC (Rs=0.76, P<0.001) and TBUT (Rs=−0.69, P<0.01) but not SIC. Intraglandular immune cells were also seen. Conclusion MGD-associated refractory symptoms and the symptom-sign disparity may be explained by clinically non-apparent, active inflammation of the palpebral conjunctiva as detected by IVCM. These patients may benefit from anti-inflammatory therapy. PMID:26088680

The zebrafish eye—a paradigm for investigating human ocular genetics

PubMed Central

Richardson, R; Tracey-White, D; Webster, A; Moosajee, M

2017-01-01

Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future. PMID:27612182

Development of infrared thermal imager for dry eye diagnosis

NASA Astrophysics Data System (ADS)

Chiang, Huihua Kenny; Chen, Chih Yen; Cheng, Hung You; Chen, Ko-Hua; Chang, David O.

2006-08-01

This study aims at the development of non-contact dry eye diagnosis based on an infrared thermal imager system, which was used to measure the cooling of the ocular surface temperature of normal and dry eye patients. A total of 108 subjects were measured, including 26 normal and 82 dry eye patients. We have observed that the dry eye patients have a fast cooling of the ocular surface temperature than the normal control group. We have developed a simplified algorithm for calculating the temperature decay constant of the ocular surface for discriminating between normal and dry eye. This study shows the diagnostic of dry eye syndrome by the infrared thermal imager system has reached a sensitivity of 79.3%, a specificity of 75%, and the area under the ROC curve 0.841. The infrared thermal imager system has a great potential to be developed for dry eye screening with the advantages of non-contact, fast, and convenient implementation.

Dental stem cells: a future asset of ocular cell therapy.

PubMed

Yam, Gary Hin-Fai; Peh, Gary Swee-Lim; Singhal, Shweta; Goh, Bee-Tin; Mehta, Jodhbir S

2015-11-10

Regenerative medicine using patient's own stem cells (SCs) to repair dysfunctional tissues is an attractive approach to complement surgical and pharmacological treatments for aging and degenerative disorders. Recently, dental SCs have drawn much attention owing to their accessibility, plasticity and applicability for regenerative use not only for dental, but also other body tissues. In ophthalmology, there has been increasing interest to differentiate dental pulp SC and periodontal ligament SC (PDLSC) towards ocular lineage. Both can commit to retinal fate expressing eye field transcription factors and generate rhodopsin-positive photoreceptor-like cells. This proposes a novel therapeutic alternative for retinal degeneration diseases. Moreover, as PDLSC shares similar cranial neural crest origin and proteoglycan secretion with corneal stromal keratoctyes and corneal endothelial cells, this offers the possibility of differentiating PDLSC to these corneal cell types. The advance could lead to a shift in the medical management of corneal opacities and endothelial disorders from highly invasive corneal transplantation using limited donor tissue to cell therapy utilizing autologous cells. This article provides an overview of dental SC research and the perspective of utilizing dental SCs for ocular regenerative medicine.

Lycopersicon esculentum lectin is a marker of transient amplifying cells in in vitro cultures of isolated limbal stem cells.

PubMed

Vergallo, C; Fonseca, T; Pizzi, G; Dini, L

2010-08-01

The maintenance of a healthy corneal epithelium under both normal and wound healing conditions is achieved by a population of stem cells (SCs) located in the basal epithelium at the corneoscleral limbus. In the light of the development of strategies for reconstruction of the ocular surface in patients with limbal stem cell deficiency, a major challenge in corneal SCs biology remains the ability to identify stem cells in situ and in vitro. To date, not so much markers exist for the identification of different phenotypes. CESCs (corneal epithelial stem cells) isolated from limbal biopsies were maintained in primary culture for 14 days and stained with Hoechst and a panel of FITC-conjugated lectins. All lectins, with the exception of Lycopersicon esculentum, labelled CESCs irrespective of the degree of differentiation. Lycopersicon esculentum, that binds N-acetylglucosamine oligomers, labelled intensely only the surface of TACs (single corneal epithelial stem cells better than colonial cells). These results suggest that Lycopersicon esculentum lectin is a useful and easy-to-use marker for the in vitro identification of TACs (transient amplifying cells) in cultures of isolated CESCs. Copyright 2010. Published by Elsevier Ltd.

[Clinical and histopathologic analysis of superficial tissue proliferation following the implantation of keratoprosthesis].

PubMed

Dong, Ying; Huang, Yi-Fei; Liu, Qian; DU, Gai-Ping

2011-05-01

To investigate the clinical and histopathologic features of the superficial tissue proliferation (STP) following the implantation of MICOF keratoprosthesis, and to analyze the formation and treatment of STP. Retrospective study. Eighty-five patients (85 eyes) received MICOF keratoprosthesis surgery from January 2000 through December 2009 in General Hospital of PLA, which included 72 males and 13 females. The mean age of the patients was (45 ± 15) years. Preoperative diagnoses were ocular burn (56 eyes), end-stage of autoimmune dry eye (14 eyes), severe ocular trauma (10 eyes) and repeated graft failure (5 eyes). Postoperatively, STPs of Kpro were observed and treated. The membranes anterior to the optical cylinder were removed and investigated by histological and immunohistochemical methods, and anterior segment specimens from normal eyes were taken as control. Twenty-two (26%) patients presented STP during the follow-up, and proliferations occurred ranging from 2 to 63 months (median, 7 months). The incident rates of STP were 34% (19/56 eyes) in burned eyes, 14% (2/14 eyes) in end-stage dry eye, 10% (1/10 eyes) in severe mechanical ocular trauma, and none in repeated grafts failure. Difference among four groups did not arrive significance statistically (χ(2) = 5.93, P = 0.11). The epithelial proliferations were observed in 11 patients, which were removed easily. To prevent from recurrence, the height of the cylinder was adjusted. Other 4 patients underwent ultra-high frequency ocular surface plastic operation and 7 patients received membranectomy. Histologically, the superficial proliferative membrane was composed of proliferative epithelium and fibrovascular tissue incorporating inflammatory cells. The immunohistochemical staining demonstrated the expression of PCNA increased in the epithelium, compared with control cornea and conjunctiva. Many vimentin-positive fibroblasts and a few α-SMA-positive myofibroblasts presented in the interstitial tissue, and the numbers of CD45RO-positive T cells, CD11c-positive dendritic cells, and CD68-positive macrophages were increased in proliferative membranes. The tissue proliferation around optical cylinder results in membrane formation anterior to the Kpro. The excessive inflammation at the prosthesis-corneal junction and the unsuited height of the optical cylinder might have been the main reasons of STP.

Role of radiation therapy in the management of ocular reticulum cell sarcoma. [Efficacy and complications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Margolis, L.; Fraser, R.; Lichter, A.

Nine patients with ocular lymphomas were seen in the Department of Ophthalmology and the Division of Radiation Oncology at UCSF and Ralph K. Davies Medical Center, San Francisco, from 1968 through 1974. Six of the 9 patients had visual symptoms as the first manifestation of their disease. Eight of the 9 patients developed intracranial lymphoma at some time during the course of the disease. Despite lymphoma work-up including bone marrow biopsies and lymphangiogram, only 1 patient was found to have documented systemic involvement. The diagnosis of ocular lymphoma was based on pathologic material from the eye in 5 cases ormore » from central nervous system biopsy in 4 patients in association with tumor cell infiltrates in the retina and vitreous clouding. Radiation therapy to the eyes improved vision in 10 of 13 eyes treated in 8 patients. The usual dose was in the range of 3500 to 4500 rads given over 4 to 5 weeks. In addition, 7 patients received central nervous system irradiation. Review of the literature reinforced the findings of this series showing the frequent association of ocular lymphoma with intracranial lymphoma and the rare systemic dissemination. This disease process has previously been referred to as ocular reticulum cell sarcoma.« less

Design and evaluation of moxifloxacin hydrochloride ocular inserts.

PubMed

Pawar, Pravin K; Katara, Rajesh; Majumdar, Dipak K

2012-03-01

The objective of the present investigation was to prepare and evaluate ocular inserts of moxifloxacin. An ocular insert was made from an aqueous dispersion of moxifloxacin, sodium alginate, polyvinyl alcohol, and dibutyl phthalate by the film casting method. The ocular insert (5.5 mm diameter) was cross-linked by CaCl2 and was coated with Eudragit S-100, RL-100, RS-100, E-100 or L-100. The in vitro drug drainage/permeation studies were carried out using an all-glass modified Franz diffusion cell. The drug concentration and mucoadhesion time of the ocular insert were found satisfactory. Cross-linking and coating with polymers extended the drainage from inserts. The cross-linked ocular insert coated with Eudragit RL-100 showed maximum drug permeation compared to other formulations.

Ocular diseases: immunological and molecular mechanisms

PubMed Central

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation. PMID:27275439

Ocular diseases: immunological and molecular mechanisms.

PubMed

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation.

Vision-guided ocular growth in a mutant chicken model with diminished visual acuity

PubMed Central

Ritchey, Eric R.; Zelinka, Christopher; Tang, Junhua; Liu, Jun; Code, Kimberly A.; Petersen-Jones, Simon; Fischer, Andy J.

2012-01-01

Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein β3 (GNB3), also known as transducin β3 or Gβ3. The mutation in GNB3 destabilizes the protein and causes a loss of Gβ3 from photoreceptors and ON-bipolar cells. (Ritchey et al. 2010)FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gβ3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gβ3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus. PMID:22824538

The cholesterol-dependent cytolysin pneumolysin from Streptococcus pneumoniae binds to lipid raft microdomains in human corneal epithelial cells.

PubMed

Taylor, Sidney D; Sanders, Melissa E; Tullos, Nathan A; Stray, Stephen J; Norcross, Erin W; McDaniel, Larry S; Marquart, Mary E

2013-01-01

Streptococcus pneumoniae (pneumococcus) is an opportunistic bacterial pathogen responsible for causing several human diseases including pneumonia, meningitis, and otitis media. Pneumococcus is also a major cause of human ocular infections and is commonly isolated in cases of bacterial keratitis, an infection of the cornea. The ocular pathology that occurs during pneumococcal keratitis is partly due to the actions of pneumolysin (Ply), a cholesterol-dependent cytolysin produced by pneumococcus. The lytic mechanism of Ply is a three step process beginning with surface binding to cholesterol. Multiple Ply monomers then oligomerize to form a prepore. The prepore then undergoes a conformational change that creates a large pore in the host cell membrane, resulting in cell lysis. We engineered a collection of single amino acid substitution mutants at residues (A370, A406, W433, and L460) that are crucial to the progression of the lytic mechanism and determined the effects that these mutations had on lytic function. Both Ply(WT) and the mutant Ply molecules (Ply(A370G), Ply(A370E), Ply(A406G), Ply(A406E), Ply(W433G), Ply(W433E), Ply(W433F), Ply(L460G), and Ply(L460E)) were able to bind to the surface of human corneal epithelial cells (HCECs) with similar efficiency. Additionally, Ply(WT) localized to cholesterol-rich microdomains on the HCEC surface, however, only one mutant (Ply(A370G)) was able to duplicate this behavior. Four of the 9 mutant Ply molecules (Ply(A370E), Ply(W433G), Ply(W433E), and Ply(L460E)) were deficient in oligomer formation. Lastly, all of the mutant Ply molecules, except Ply(A370G), exhibited significantly impaired lytic activity on HCECs. The other 8 mutants all experienced a reduction in lytic activity, but 4 of the 8 retained the ability to oligomerize. A thorough understanding of the molecular interactions that occur between Ply and the target cell, could lead to targeted treatments aimed to reduce the pathology observed during pneumococcal keratitis.

The Cholesterol-Dependent Cytolysin Pneumolysin from Streptococcus pneumoniae Binds to Lipid Raft Microdomains in Human Corneal Epithelial Cells

PubMed Central

Taylor, Sidney D.; Sanders, Melissa E.; Tullos, Nathan A.; Stray, Stephen J.; Norcross, Erin W.; McDaniel, Larry S.; Marquart, Mary E.

2013-01-01

Streptococcus pneumoniae (pneumococcus) is an opportunistic bacterial pathogen responsible for causing several human diseases including pneumonia, meningitis, and otitis media. Pneumococcus is also a major cause of human ocular infections and is commonly isolated in cases of bacterial keratitis, an infection of the cornea. The ocular pathology that occurs during pneumococcal keratitis is partly due to the actions of pneumolysin (Ply), a cholesterol-dependent cytolysin produced by pneumococcus. The lytic mechanism of Ply is a three step process beginning with surface binding to cholesterol. Multiple Ply monomers then oligomerize to form a prepore. The prepore then undergoes a conformational change that creates a large pore in the host cell membrane, resulting in cell lysis. We engineered a collection of single amino acid substitution mutants at residues (A370, A406, W433, and L460) that are crucial to the progression of the lytic mechanism and determined the effects that these mutations had on lytic function. Both PlyWT and the mutant Ply molecules (PlyA370G, PlyA370E, PlyA406G, PlyA406E, PlyW433G, PlyW433E, PlyW433F, PlyL460G, and PlyL460E) were able to bind to the surface of human corneal epithelial cells (HCECs) with similar efficiency. Additionally, PlyWT localized to cholesterol-rich microdomains on the HCEC surface, however, only one mutant (PlyA370G) was able to duplicate this behavior. Four of the 9 mutant Ply molecules (PlyA370E, PlyW433G, PlyW433E, and PlyL460E) were deficient in oligomer formation. Lastly, all of the mutant Ply molecules, except PlyA370G, exhibited significantly impaired lytic activity on HCECs. The other 8 mutants all experienced a reduction in lytic activity, but 4 of the 8 retained the ability to oligomerize. A thorough understanding of the molecular interactions that occur between Ply and the target cell, could lead to targeted treatments aimed to reduce the pathology observed during pneumococcal keratitis. PMID:23577214

Chronic dry eye in PRK and LASIK: manifestations, incidence and predictive factors

PubMed Central

Bower, Kraig S.; Sia, Rose K.; Ryan, Denise S.; Mines, Michael J.; Dartt, Darlene A.

2017-01-01

Purpose To evaluate dry eye manifestations following photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) and determine the incidence and predictive factors of chronic dry eye using a set of dry eye criteria. Setting Walter Reed Army Medical Center, Washington, DC, USA Methods This is a prospective non-randomized clinical study of 143 active duty U.S. Army personnel aged 29.9±5.2 years with myopia or myopic astigmatism (manifest spherical equivalent −3.83±1.96 diopters) undergoing either PRK or LASIK. Dry eye evaluation was performed pre- and postoperatively. Main outcome measures included dry eye manifestations, incidence, and predictive factors of chronic dry eye. Results Schirmer scores, corneal sensitivity, ocular surface staining, surface regularity index (SRI), and responses to dry eye questionnaire significantly changed over time after PRK. After LASIK, significant changes were observed in tear breakup time, corneal sensitivity, ocular surface staining, and responses to questionnaire. At twelve months postoperatively, 5.0% of PRK and 0.8% of LASIK participants developed chronic dry eye. Regression analysis showed preoperatively lower Schirmer score will significantly influence development of chronic dry eye after PRK whereas preoperatively lower Schirmer score or higher ocular surface staining score will significantly influence the occurrence of chronic dry eye after LASIK. Conclusions Chronic dry eye is uncommon after PRK and LASIK. Ocular surface and tear film characteristics during preoperative examination may help predict chronic dry eye development in PRK and LASIK. PMID:26796443

[Development of non-invasive clinical examination methods for the anterior segment of the eye and their clinical significance].

PubMed

Sawa, Mitsuru

2011-03-01

1. Slit-lamp microscopy is a principal ophthalmic clinical method, because it provides microscopic findings of the anterior segment of the eye noninvasively. Its findings, however, are qualitative and there are large inter-observer variations in their evaluation. Furthermore, slit-lamp microscopy provides morphological findings, but a functional evaluation is difficult. We developed two novel methods that establish a qualitative methodology of the slit-lamp microscope and the pathophysiology of the anterior segment of the eye. One is the flare-cell photometer to evaluate flare and cells in the aqueous humor of the eye and the other is an immunohistochemical examination method using tear fluid to evaluate ocular surface disorders. The comprehensive evaluation of these studies is herein overviewed. 2. INNOVATION OF THE FLARE-CELL PHOTOMETER AND ITS CLINICAL SIGNIFICANCE: The breakdown of the blood-aqueous barrier (BAB) causes an increase in protein (flare) and leakage of blood cells (cell) into the aqueous humor of the eye and the severity of BAB breakdown has a positive correlation with the intensity of flare and cells. The flare and cells in the aqueous can be observed qualitatively by slit-lamp microscopy. These findings are primarily distinguished in optics by light scattering. Therefore, detection of the intensity of light scattering due to flare and cells can evaluate the BAB function. The flare-cell photometer comprises 3 novel components: a laser beam system as an incident light, a photomultiplier to detect scattered light intensity and a computer-assisted system to operate the whole system and analyze detected scattered light signals due to flare and cells. The instrument enables us to quantitatively analyze the flare and cells non-invasively and accurately with a wide dynamic measurement range, resulting in a repeated examination of each individual case. It also enables the evaluation of inflammation in the aqueous not only postoperatively but also in endogenous uveitis, evaluation of the effects of anti-inflammatory drugs on BAB and evaluation of aqueous humor dynamics. Furthermore, repeating the examination can minimize inter-individual variations and reduce the number of animals in animal experiments. 3. Sampling of tears can be performed noninvasively, but the obtainable volume is limited. Therefore, a determination of targeting biomarkers and a development of their micro-volume analysis methods play a crucial role in pathophysiological studies of the ocular surface. Targeting biomarkers should be determined according to the various specified bioactive substances such as eosinophil cationic protein (ECP), cytokines and others. A number of microvolume analysis methods, such as chemiluminescent enzyme immunoassay, immunochromatography, micro-array system and polymerase chain reaction method are used. Objective disorders in the studies include allergic conjunctivitis and infectious diseases such as herpetic keratitis. Quantitative evaluation methods for ECP concentration, antigen-specific secretory IgA in allergic diseases and herpetic keratitis, herpes simplex virus-DNA and cytokine and chemokine profile in tear fluid sampled by filter paper method were investigated. We developed a clinically applicable quantitative immunochemical method for ECP concentration in tear fluid. The results revealed that tear fluid analysis using the above mentioned methods is a clinically useful to investigate the pathophysiology of the ocular surface. 4. Laser flare-cell photometer and tear fluid analysis are potent clinical quantitative methods to investigate the pathophysiology of the anterior segment of the eye.

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

PubMed

Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

2018-05-18

Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.

HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability.

PubMed

Qian, Yi-Wen; Li, Chuan; Jiang, Ai-Ping; Ge, Shengfang; Gu, Ping; Fan, Xianqun; Li, Tai-Sheng; Jin, Xia; Wang, Jian-Hua; Wang, Zhi-Liang

2016-10-28

Approximately 70% of HIV-1 infected patients acquire ocular opportunistic infections and manifest eye disorders during the course of their illness. The mechanisms by which pathogens invade the ocular site, however, are unclear. Under normal circumstances, vascular endothelium and retinal pigment epithelium (RPE), which possess a well developed tight junction complex, form the blood-retinal barrier (BRB) to prevent pathogen invasion. We hypothesize that disruption of the BRB allows pathogen entry into ocular sites. The hypothesis was tested using in vitro models. We discovered that human RPE cells could bind to either HIV-1 gp120 glycoproteins or HIV-1 viral particles. Furthermore, the binding was mediated by dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) expressed on RPE cells. Upon gp120 binding to DC-SIGN, cellular NF-κB signaling was triggered, leading to the induction of matrix metalloproteinases, which subsequently degraded tight junction proteins and disrupted the BRB integrity. DC-SIGN knockdown or prior blocking with a specific antibody abolished gp120-induced matrix metalloproteinase expression and reduced the degradation of tight junction proteins. This study elucidates a novel mechanism by which HIV, type 1 invades ocular tissues and provides additional insights into the translocation or invasion process of ocular complication-associated pathogens. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Allergic conjunctivitis: a comprehensive review of the literature

PubMed Central

2013-01-01

Ocular allergy represents one of the most common conditions encountered by allergists and ophthalmologists. Allergic conjunctivitis is often underdiagnosed and consequently undertreated. Basic and clinical research has provided a better understanding of the cells, mediators, and immunologic events, which occur in ocular allergy. New pharmacological agents have improved the efficacy and safety of ocular allergy treatment. An understanding of the immunologic mechanisms, clinical features, differential diagnosis, and treatment of ocular allergy may be useful to all specialists who deal with these patients. The purpose of this review is to systematically review literature underlining all the forms classified as ocular allergy: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratocongiuntivitis, contact allergy, and giant papillary conjunctivitis. PMID:23497516

Genetic Testing as a Tool to Identify Horses with or at Risk for Ocular Disorders.

PubMed

Bellone, Rebecca R

2017-12-01

Advances in equine genetics and genomics resources have enabled the understanding of some inherited ocular disorders and ocular manifestations. These ocular disorders include congenital stationary night blindness, equine recurrent uveitis, multiple congenital ocular anomalies, and squamous cell carcinoma. Genetic testing can identify horses with or at risk for disease and thus can assist in clinical management. In addition, genetic testing can identify horses that are carriers and thus can inform breeding decisions. Use of genetic tests in management and breeding decisions should aid in reducing the incidence of these disorders and improving the outcomes for horses at highest risk. Copyright © 2017 Elsevier Inc. All rights reserved.

Alkali Burn of the Ocular Surface Associated With a Commonly Used Antifog Agent for Eyewear: Two Cases and a Review of Previous Reports.

PubMed

Welling, John D; Pike, Evan C; Mauger, Thomas F

2016-02-01

To report 2 cases of ocular chemical burns associated with the use of a swim goggle antifog agent and to review the literature for this and similar antifog products. Case reports and systematic review of the medical literature, material safety data, product safety reports, and consumer reviews. Two males, one 46 years and the other 41 years, were referred to our clinic with chemical burns of the ocular surface after using the same goggle antifog agent while swimming in a triathlon. Both sustained significant epithelial defects. Fortunately, with prompt treatment, both of our patients returned to their baseline vision within a few weeks without suffering sight-threatening complications. These are the first cases of ocular chemical burn secondary to use of an eyewear antifog agent to be reported in the medical literature. Similar reports found in consumer forums suggest that our cases are not isolated and these products may have the potential to cause vision-threatening chemical burns.

Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice.

PubMed

Curtis, Lauren M; Datiles, Manuel B; Steinberg, Seth M; Mitchell, Sandra A; Bishop, Rachel J; Cowen, Edward W; Mays, Jacqueline; McCarty, John M; Kuzmina, Zoya; Pirsl, Filip; Fowler, Daniel H; Gress, Ronald E; Pavletic, Steven Z

2015-09-01

Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test and National Institutes of Health 0-3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (P<0.0001) and Schirmer's tear test (P<0.0001) were independent predictors of ocular chronic graft-versus-host disease (sensitivity 93.0%, specificity 92.2%). The Lee ocular subscale was the strongest predictor of active ocular chronic graft-versus-host disease (P<0.0001) (sensitivity 68.5%, specificity 82.6%). Ophthalmology specialist measures that were most strongly predictive of diagnosis in a multivariate model were Oxford grand total staining (P<0.0001) and meibomian score (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure. Copyright© Ferrata Storti Foundation.

Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice

PubMed Central

Curtis, Lauren M.; Datiles, Manuel B.; Steinberg, Seth M.; Mitchell, Sandra A.; Bishop, Rachel J.; Cowen, Edward W.; Mays, Jacqueline; McCarty, John M.; Kuzmina, Zoya; Pirsl, Filip; Fowler, Daniel H.; Gress, Ronald E.; Pavletic, Steven Z.

2015-01-01

Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer’s tear test and National Institutes of Health 0–3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (P<0.0001) and Schirmer’s tear test (P<0.0001) were independent predictors of ocular chronic graft-versus-host disease (sensitivity 93.0%, specificity 92.2%). The Lee ocular subscale was the strongest predictor of active ocular chronic graft-versus-host disease (P<0.0001) (sensitivity 68.5%, specificity 82.6%). Ophthalmology specialist measures that were most strongly predictive of diagnosis in a multivariate model were Oxford grand total staining (P<0.0001) and meibomian score (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure. PMID:26088932

Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye.

PubMed

Jiang, Xiaodan; Lv, Huibin; Qiu, Weiqiang; Liu, Ziyuan; Li, Xuemin; Wang, Wei

2015-01-01

Dry eye is a chronic inflammatory ocular surface disease with high prevalence. The current therapies for dry eye remain to be unspecific and notcomprehensive. This study aims to explore safety and efficacy of a novel treatment - subconjunctival injection of bevacizumab - in dry eye patients. Sixty-four eyes of 32 dry eye patients received subconjunctival injection of 100 μL 25 mg/mL bevacizumab. Dry eye symptoms, signs (corrected visual acuity, intraocular pressure, conjunctival vascularity, corneal staining, tear break-up time, Marx line score, and blood pressure), and conjunctival impression cytology were evaluated 3 days before and 1 week, 1 month, and 3 months after injection. Significant improvements were observed in dry eye symptoms, tear break-up time, and conjunctival vascularization area at all the visits after injection compared to the baseline (P<0.05). The density of the goblet cell increased significantly at 1 month and 3 months after injection (P<0.05). There was no visual and systemic threat observed in any patient. Subconjunctival injection of 100 μL 25 mg/mL bevacizumab is a safe and efficient treatment for ocular surface inflammation of dry eye disease.

What We Have Learned from Animal Models of Dry Eye

PubMed Central

Stern, Michael E.; Pflugfelder, Stephen C.

2017-01-01

Animal models have proved valuable to investigate the pathogenesis of dry eye disease, identify therapeutic targets and the efficacy of candidate therapeutics for dry eye. Pharmacological inhibition of the lacrimal functional unit and exposure of the mouse eye to desiccating stress was found to activate innate immune pathways, promote dendritic cell maturation and initiate an adaptive T cell response to ocular surface antigens. Disease relevant mediators and pathways have been identified through use of genetically altered mice, specific inhibitors and adoptive transfer of desiccating stress primed CD4+ T cells to naïve recipients. Findings from mouse models have elucidated the mechanism of action of cyclosporine A and the rationale for developing lifitegrast, the two currently approved therapeutics in the US. PMID:28282318

In Vivo Confocal Microscopy of the Ocular Surface: From Bench to Bedside

PubMed Central

Villani, Edoardo; Baudouin, Christophe; Efron, Nathan; Hamrah, Pedram; Kojima, Takashi; Patel, Sanjay V.; Pflugfelder, Stephen C.; Zhivov, Andrey; Dogru, Murat

2014-01-01

In vivo confocal microscopy (IVCM) is an emerging technology that provides minimally invasive, high resolution, steady-state assessment of the ocular surface at the cellular level. Several challenges still remain but, at present, IVCM may be considered a promising technique for clinical diagnosis and management. This mini-review summarizes some key findings in IVCM of the ocular surface, focusing on recent and promising attempts to move “from bench to bedside”. IVCM allows prompt diagnosis, disease course follow-up, and management of potentially blinding atypical forms of infectious processes, such as acanthamoeba and fungal keratitis. This technology has improved our knowledge of corneal alterations and some of the processes that affect the visual outcome after lamellar keratoplasty and excimer keratorefractive surgery. In dry eye disease, IVCM has provided new information on the whole-ocular surface morphofunctional unit. It has also improved understanding of pathophysiologic mechanisms and helped in the assessment of prognosis and treatment. IVCM is particularly useful in the study of corneal nerves, enabling description of the morphology, density, and disease- or surgically induced alterations of nerves, particularly the subbasal nerve plexus. In glaucoma, IVCM constitutes an important aid to evaluate filtering blebs, to better understand the conjunctival wound healing process, and to assess corneal changes induced by topical antiglaucoma medications and their preservatives. IVCM has significantly enhanced our understanding of the ocular response to contact lens wear. It has provided new perspectives at a cellular level on a wide range of contact lens complications, revealing findings that were not previously possible to image in the living human eye. The final section of this mini-review provides a focus on advances in confocal microscopy imaging. These include 2D wide-field mapping, 3D reconstruction of the cornea and automated image analysis. PMID:24215436

Sleep and mood disorders in dry eye disease and allied irritating ocular diseases.

PubMed

Ayaki, Masahiko; Kawashima, Motoko; Negishi, Kazuno; Kishimoto, Taishiro; Mimura, Masaru; Tsubota, Kazuo

2016-03-01

The aim of the present study was to evaluate sleep and mood disorders in patients with irritating ocular diseases. The study design was a cross-sectional/case-control study conducted in six eye clinics. Out of 715 outpatients diagnosed with irritating ocular surface diseases and initially enrolled, 301 patients with dry eye disease (DED) and 202 age-matched control participants with other ocular surface diseases were analyzed. The mean Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) scores were 6.4 ± 3.2 and 11.1 ± 5.7 for severe DED (n = 146), 5.5 ± 3.3 and 9.8 ± 4.0 for mild DED (n = 155), 5.5 ± 3.1 and 9.5 ± 6.6 for chronic conjunctivitis (n = 124), and 5.0 ± 3.3 and 8.9 ± 5.3 for allergic conjunctivitis (n = 78). There were significant differences among these diagnostic groups for PSQI (P < 0.05). Regression analysis of patients with DED revealed the PSQI and HADS scores were significantly correlated with the severity of DED (P < 0.05). Our results demonstrate that sleep quality in patients with DED is significantly worse than in patients with other irritating ocular surface diseases and it is correlated with the severity of DED.

Episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery - recent research advances and patents.

PubMed

Gilger, Brian C; Mandal, Abhirup; Shah, Sujay; Mitra, Ashim K

2014-01-01

Subconjunctival/episcleral, intrascleral, and suprachoroidal routes of drug delivery for treatment of posterior segment eye diseases have become more feasible and popular in the past few years. These routes have the advantage of bypassing the main barriers to topical drug penetration, the ocular surface epithelium, the conjunctivallymphatics, and in the case of deep intrascleral and suprachoroidial delivery, the sclera barrier. Many ocular drug delivery application devices, drug delivery methods, and therapeutics that have been developed for intravitreal use can also be used subconjunctivally, intrasclerally, and in the suprachoroidal space. Alternatively, site-specific devices, such microneedles, and therapeutics, such as hydrogel matrices, have been developed to enhance ocular drug delivery. This manuscript will review the recent research advances and patents on episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery.

Nontuberculous Mycobacterial Ocular Infections: A Systematic Review of the Literature

PubMed Central

Kheir, Wajiha J.; Sheheitli, Huda; Abdul Fattah, Maamoun; Hamam, Rola N.

2015-01-01

Nontuberculous or atypical mycobacterial ocular infections have been increasing in prevalence over the past few decades. They are known to cause periocular, adnexal, ocular surface and intraocular infections and are often recalcitrant to medical therapy. These infections can potentially cause detrimental outcomes, in part due to a delay in diagnosis. We review 174 case reports and series on nontuberculous mycobacterial (NTM) ocular infections and discuss etiology, microbiology, risk factors, diagnosis, clinical presentation, and treatment of these infections. History of interventions, trauma, foreign bodies, implants, contact lenses, and steroids are linked to NTM ocular infections. Steroid use may prolong the duration of the infection and cause poorer visual outcomes. Early diagnosis and initiation of treatment with multiple antibiotics are necessary to achieve the best visual outcome. PMID:26106601

The involvement of autoimmunity against retinal antigens in determining disease severity in toxoplasmosis.

PubMed

Vallochi, Adriana Lima; da Silva Rios, Lília; Nakamura, Marceli Vicente; Silveira, Cláudio; Muccioli, Cristina; Martins, Maria Cristina; Belfort, Rubens; Rizzo, Luiz Vicente

2005-02-01

Ocular lesions are frequent in various individuals infected with Toxoplasma gondii. Disease intensity in ocular toxoplasmosis varies greatly between patients. Autoimmunity has been suggested as a possible component to retinal destruction. Immunologic parameters in the response to retina antigens were evaluated in infected persons with and without ocular lesions and in non-infected controls. Subjects were divided into groups on the basis of titers of serum antibodies to T. gondii, presence and severity of ocular lesions, and clinical history. Peripheral blood mononuclear cells from patients with mild disease responded to one or more retinal antigens with a significantly higher frequency than patients without disease or with severe disease. Interestingly, the cytokines produced by the proliferating mononuclear cells did not follow any specific patterns, except for the fact that IL-4 and IL-5 were seldom detected. Our results suggest that although the presence of an immune response towards autoantigens is not protective against the development of ocular lesions by the T. gondii, it may protect against the development of severe disease.

Corneal Epitheliopathy After Trauma by Fake Snow Powder in a 7-year-old Child

PubMed Central

Al-Amry, Mohammad A.; Al-Ghadeer, Huda A.

2016-01-01

Fake snow is a polymer of sodium polyacrylates used in games and celebrations. Despite the product leaflet that indicates safety, contact with the ocular surface can cause injury. We report a case of a child with corneal epitheliopathy due to a chemical burn injury after ocular surface contact with fake snow. The case was managed with epithelial debridement and a bandage contact lenses and topical antibiotics with complete resolution. PMID:27555717

Effects of the rigid gas permeable contact lense use on tear and ocular surface among keratoconus patients.

PubMed

Yuksel Elgin, Cansu; Iskeleli, Guzin; Aydin, Ovgu

2018-06-01

To investigate changes in tear and ocular surface of patients with keratoconus using rigid gas permeable contact lenses (RGPCL) and compare them against keratoconus patients who were not using lenses as well as a control group of healthy subjects. 24 keratoconus patients using RGPCL (Group 1) 22 patients who were not using lenses (Group 3) and 21 healthy subjects (Group 3) were included in the study. Subjective complaints about the subjects' eyes have been investigated using the ocular-surface disease index (OSDI). After the control of best-corrected visual acuity, anterior chamber and fundus examinations were performed. Schirmer (p-value=0.01) and tear break up mean comparison tests (p-value=0.002) revealed significant differences across different groups but tear osmolarity analysis did not (p-value >0.05). Oxford and OSDI scores were compatible with Schirmer and tear break up test comparisons. (for both p-value=0.001) Moreover, no statistical differences were seen in impression cytology measures between groups. (p-value >0.05) CONCLUSIONS: The erosion in the tear film stability is in line with the erosion in the ocular surface epithelium. Taking into account the statistical indifference between the impression cytology measures across groups, the break up time differences may be attributed to the collagen destruction in tear. Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Treatment of ocular rosacea: comparative study of topical cyclosporine and oral doxycycline.

PubMed

Arman, Aysegul; Demirseren, Duriye Deniz; Takmaz, Tamer

2015-01-01

To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints. One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline. Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes (P<0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs (P=0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group (P<0.05). Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.

Gelatin-Based Materials in Ocular Tissue Engineering.

PubMed

Rose, James B; Pacelli, Settimio; Haj, Alicia J El; Dua, Harminder S; Hopkinson, Andrew; White, Lisa J; Rose, Felicity R A J

2014-04-17

Gelatin has been used for many years in pharmaceutical formulation, cell culture and tissue engineering on account of its excellent biocompatibility, ease of processing and availability at low cost. Over the last decade gelatin has been extensively evaluated for numerous ocular applications serving as cell-sheet carriers, bio-adhesives and bio-artificial grafts. These different applications naturally have diverse physical, chemical and biological requirements and this has prompted research into the modification of gelatin and its derivatives. The crosslinking of gelatin alone or in combination with natural or synthetic biopolymers has produced a variety of scaffolds that could be suitable for ocular applications. This review focuses on methods to crosslink gelatin-based materials and how the resulting materials have been applied in ocular tissue engineering. Critical discussion of recent innovations in tissue engineering and regenerative medicine will highlight future opportunities for gelatin-based materials in ophthalmology.

Gelatin-Based Materials in Ocular Tissue Engineering

PubMed Central

Rose, James B.; Pacelli, Settimio; El Haj, Alicia J.; Dua, Harminder S.; Hopkinson, Andrew; White, Lisa J.; Rose, Felicity R. A. J.

2014-01-01

Gelatin has been used for many years in pharmaceutical formulation, cell culture and tissue engineering on account of its excellent biocompatibility, ease of processing and availability at low cost. Over the last decade gelatin has been extensively evaluated for numerous ocular applications serving as cell-sheet carriers, bio-adhesives and bio-artificial grafts. These different applications naturally have diverse physical, chemical and biological requirements and this has prompted research into the modification of gelatin and its derivatives. The crosslinking of gelatin alone or in combination with natural or synthetic biopolymers has produced a variety of scaffolds that could be suitable for ocular applications. This review focuses on methods to crosslink gelatin-based materials and how the resulting materials have been applied in ocular tissue engineering. Critical discussion of recent innovations in tissue engineering and regenerative medicine will highlight future opportunities for gelatin-based materials in ophthalmology. PMID:28788609

Topical steroid and non-steroidal anti-inflammatory drugs inhibit inflammatory cytokine expression on the ocular surface in the botulinum toxin B-induced murine dry eye model.

PubMed

Zhu, Lei; Zhang, Cheng; Chuck, Roy S

2012-01-01

To evaluate the effect of the topical steroid, fluorometholone, and the non-steroidal anti-inflammatory drugs (NSAIDs), nepafenac and ketorolac, on inflammatory cytokine expression of the ocular surface in the botulium toxin B-induced murine dry eye model. Topical artificial tears (0.5% carboxymethylcellulose sodium), 0.1% fluorometholone, 0.1% nepafenac, and 0.4% ketorolac were applied 3 times per day in a dry eye mouse model 1 week after intralacrimal botulium toxin B (BTX-B) or saline (sham) injection. Tear production and corneal fluorescein staining were evaluated in all groups before injection at baseline and at 3 time points up to 4 weeks after injection. The pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were evaluated by immunohistochemistry. BTX-B-injected mice showed significantly decreased aqueous tear production and increased corneal fluorescein staining at the 1 and 2 week time points compared with normal control and saline-injected mice. In the BTX-B-injected mice, immunofluorescent staining for TNF-α and IL-1β in corneal and conjunctival epithelial cells increased significantly at the 2 and 4 week time points compared to that of normal and saline-injected mice, and returned to normal levels at the 4 week time point. Topical fluorometholone significantly improved corneal surface staining in the BTX-B-injected mice after 1 week of treatment, and increased the tear production within 2 weeks, but without statistical significant difference. Topical fluorometholone significantly decreased the staining of TNF-α and IL-1β in corneal and conjunctival epithelia after 1-week treatment. Topical artificial tears, 0.1% nepafenac, and 0.4% ketorolac did not show obvious effects on tear production, corneal surface staining, and levels of IL-1β and TNF-α expression in normal, and BTX-B-injected dry eye mice. Topical fluorometholone caused suppression of inflammatory cytokine expression on the ocular surface in the Botulium toxin B-induced murine dry eye model, while topical NSAIDs demonstrated no clearly beneficial effects.

Annexin A2 in Proliferative Vitreoretinopathy

DTIC Science & Technology

2016-10-01

migrate in the presence of macrophages in an in vitro system. In addition, analysis of human retinal tissue from subjects undergoing ocular surgery... tissue from subjects undergoing ocular surgery for PVR reveals the presence of A2- immunoreactive cells that express both macrophage and RPE cell...greatly attenuated in the absence of annexin A2. Task 2: Macrophage depletion and tissue specific knockout. We have completed the characterization

Clinical and laboratory characteristics of ocular syphilis: a new face in the era of HIV co-infection.

PubMed

Lee, Sun Young; Cheng, Vincent; Rodger, Damien; Rao, Narsing

2015-12-01

Ocular syphilis is reemerging as an important cause of uveitis in the new era of common co-infection with HIV. This study will reveal the clinical and laboratory characteristics in the group of individuals co-infected with ocular syphilis and HIV compared with HIV-negative individuals. In this retrospective observational case series, medical records of patients diagnosed with ocular syphilis with serologic support from 2008 to 2014 were reviewed. Ocular and systemic manifestation and laboratory profiles were reviewed. Twenty-nine eyes of 16 consecutive patients (10 HIV-positive and 6 HIV-negative) were included. All patients were males, and mean age of onset for ocular syphilis was 43 (mean 42.65 ± 13.13). In both HIV-positive and HIV-negative groups, ocular manifestations of syphilis were variable including anterior uveitis (4 eyes), posterior uveitis (8 eyes), panuveitis (13 eyes), and isolated papillitis (4 eyes). In HIV-positive patients, panuveitis was the most common feature (12/18 eyes, 67 %) and serum rapid plasma reagin (RPR) titers were significantly higher (range 1:64-1:16,348; mean 1:768; p = 0.018) than in HIV-negative patients. Upon the diagnosis of ocular syphilis in HIV-positive patients, HIV-1 viral load was high (median 206,887 copies/ml) and CD4 cell count ranged from 127 to 535 cells/ml (mean 237 ± 142; median 137). Regardless of HIV status, cerebrospinal fluid (CSF) exam was frequently abnormal: positive CSF fluorescent treponemal antibody absorption (FTA-ABS) or Venereal Disease Research Laboratory (VDRL) test results in seven patients or either elevated CSF WBC count or elevated CSF protein in six patients. Our results reveal that the patients with ocular syphilis with high serum RPR titers may have concomitant HIV infection requiring further testing for HIV status and ocular syphilis is likely associated with the central nervous system involvement and therefore needs to be managed according to the treatment recommendations for neurosyphilis.

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva

PubMed Central

Kase, Satoru; Shinohara, Toshiya; Kase, Manabu; Ishida, Susumu

2017-01-01

It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy. PMID:28587435

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva.

PubMed

Kase, Satoru; Shinohara, Toshiya; Kase, Manabu; Ishida, Susumu

2017-06-01

It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.

Alarmins from corneal epithelial cells upregulate CCL11 and VCAM-1 in corneal fibroblasts.

PubMed

Fukuda, Ken; Ishida, Waka; Tanaka, Hiroshi; Harada, Yosuke; Matsuda, Akira; Ebihara, Nobuyuki; Fukushima, Atsuki

2013-08-27

Severe ocular allergic diseases are characterized by pronounced conjunctival inflammation triggered by T helper 2 (Th2) cells and corneal epithelial damage induced by eosinophils. To examine the role of alarmins released by damaged corneal epithelial cells in tissue eosinophilia, we investigated the effects of a supernatant derived from necrotic human corneal epithelial (HCE) cells on expression of the chemokine CCL11 (eotaxin) and the adhesion molecule VCAM-1 in human corneal fibroblasts. An alarmin preparation was obtained as the material released from HCE cells after three cycles of freezing and thawing. CCL11 released into culture medium and cell surface expression of VCAM-1 were measured with enzyme-linked immunosorbent assays, and the amounts of CCL11 and VCAM-1 mRNAs were quantitated by reverse transcription and real-time polymerase chain reaction analysis. Signaling by the transcription factor NF-κB was evaluated by immunoblot and immunofluorescence analyses. The combination of the necrotic HCE cell supernatant and either interleukin (IL)-4 or IL-13 induced synergistic increases in CCL11 release, VCAM-1 expression, and the abundance of CCL11 and VCAM-1 mRNAs in corneal fibroblasts. The necrotic HCE cell supernatant also induced NF-κB activation in corneal fibroblasts, whereas an inhibitor of NF-κB and IL-1 receptor antagonist each attenuated CCL11 release induced by the alarmin preparation and either IL-4 or IL-13. Alarmins including IL-1 released from necrotic corneal epithelial cells cooperate with Th2 cytokines to induce CCL11 production and VCAM-1 expression in corneal fibroblasts, and may thereby play an important role in tissue eosinophilia associated with ocular allergic diseases.

TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model.

PubMed

Ratay, Michelle L; Balmert, Stephen C; Acharya, Abhinav P; Greene, Ashlee C; Meyyappan, Thiagarajan; Little, Steven R

2017-12-13

Dry eye disease (DED) is a highly prevalent, ocular disorder characterized by an abnormal tear film and ocular surface. Recent experimental data has suggested that the underlying pathology of DED involves inflammation of the lacrimal functional unit (LFU), comprising the cornea, conjunctiva, lacrimal gland and interconnecting innervation. This inflammation of the LFU ultimately results in tissue deterioration and the symptoms of DED. Moreover, an increase of pathogenic lymphocyte infiltration and the secretion of pro-inflammatory cytokines are involved in the propagation of DED-associated inflammation. Studies have demonstrated that the adoptive transfer of regulatory T cells (Tregs) can mediate the inflammation caused by pathogenic lymphocytes. Thus, as an approach to treating the inflammation associated with DED, we hypothesized that it was possible to enrich the body's own endogenous Tregs by locally delivering a specific combination of Treg inducing factors through degradable polymer microspheres (TRI microspheres; TGF-β1, Rapamycin (Rapa), and IL-2). This local controlled release system is capable of shifting the balance of Treg/T effectors and, in turn, preventing key signs of dry eye disease such as aqueous tear secretion, conjunctival goblet cells, epithelial corneal integrity, and reduce the pro-inflammatory cytokine milieu in the tissue.

Comparative effect of lens care solutions on blink rate, ocular discomfort and visual performance.

PubMed

Yang, Shun-nan; Tai, Yu-chi; Sheedy, James E; Kinoshita, Beth; Lampa, Matthew; Kern, Jami R

2012-09-01

To help maintain clear vision and ocular surface health, eye blinks occur to distribute natural tears over the ocular surface, especially the corneal surface. Contact lens wearers may suffer from poor vision and dry eye symptoms due to difficulty in lens surface wetting and reduced tear production. Sustained viewing of a computer screen reduces eye blinks and exacerbates such difficulties. The present study evaluated the wetting effect of lens care solutions (LCSs) on blink rate, dry eye symptoms, and vision performance. Sixty-five adult habitual soft contact lens wearers were recruited to adapt to different LCSs (Opti-free, ReNu, and ClearCare) in a cross-over design. Blink rate in pictorial viewing and reading (measured with an eyetracker), dry eye symptoms (measured with the Ocular Surface Disease Index questionnaire), and visual discrimination (identifying tumbling E) immediately before and after eye blinks were measured after 2 weeks of adaption to LCS. Repeated measures anova and mixed model ancova were conducted to evaluate effects of LCS on blink rate, symptom score, and discrimination accuracy. Opti-Free resulted in lower dry eye symptoms (p = 0.018) than ClearCare, and lower spontaneous blink rate (measured in picture viewing) than ClearCare (p = 0.014) and ReNu (p = 0.041). In reading, blink rate was higher for ClearCare compared to ReNu (p = 0.026) and control (p = 0.024). Visual discrimination time was longer for the control (daily disposable lens) than for Opti-Free (p = 0.007), ReNu (p = 0.009), and ClearCare (0.013) immediately before the blink. LCSs differently affected blink rate, subjective dry eye symptoms, and visual discrimination speed. Those with wetting agents led to significantly fewer eye blinks while affording better ocular comfort for contact lens wearers, compared to that without. LCSs with wetting agents also resulted in better visual performance compared to wearing daily disposable contact lenses. These presumably are because of improved tear film quality. © 2012 The College of Optometrists.

Pathogenic Phenotype and Genotype of Pseudomonas aeruginosa Isolates from Spontaneous Canine Ocular Infections

PubMed Central

Ledbetter, Eric C.; Mun, James J.; Kowbel, David; Fleiszig, Suzanne M. J.

2009-01-01

Purpose This study was designed to determine whether the ability to adversely affect corneal epithelial cell health is a factor common to Pseudomonas aeruginosa keratitis strains and to assess the prevalence of each pathogenic phenotype and genotype in a canine model of naturally-acquired P. aeruginosa ocular infection. Methods P. aeruginosa ocular isolates were collected by sampling 100 dogs without disease (six isolates collected) and by sampling dogs with conjunctivitis (two isolates), endophthalmitis (one isolate), active keratitis (12 isolates), and resolved P. aeruginosa keratitis (four isolates). Phenotype was determined in vitro by quantifying corneal epithelial cell invasion by gentamicin survival assays, and cytotoxic activity by Trypan blue exclusion assays. Genotyping was performed for genes encoding the type III secreted effectors. Results The ratio of invasive to cytotoxic strains with 95% confidence intervals (CI) was 0.83 (CI, 0.42– 0.99) for conjunctival microflora isolates, 0.80 (CI, 0.54 – 0.94) for ocular infection isolates, and 1.0 (CI, 0.45–1.0) for strains isolated post-resolution of keratitis. Among ocular infection isolates, invasive and cytotoxic strains were significantly (P ≤ 0.02) associated with older and younger dogs, respectively. Visible adverse effects on epithelial cells were significantly (P ≤ 0.03) more frequent for keratitis strains (6/12) than other strains (1/13), but only three of these keratitis strains and the single non-keratitis strain possessed ExoU. Conclusions Invasive strains predominated in the dogs of this study. Only keratitis strains had visible adverse effects on epithelial cells without overt cytotoxicity, suggesting virulence strategies affecting live corneal epithelial cell health are selected for among keratitis strains. PMID:18836164

Gene therapy for ocular diseases meditated by ultrasound and microbubbles (Review)

PubMed Central

WAN, CAIFENG; LI, FENGHUA; LI, HONGLI

2015-01-01

The eye is an ideal target organ for gene therapy as it is easily accessible and immune-privileged. With the increasing insight into the underlying molecular mechanisms of ocular diseases, gene therapy has been proposed as an effective approach. Successful gene therapy depends on efficient gene transfer to targeted cells to prove stable and prolonged gene expression with minimal toxicity. At present, the main hindrance regarding the clinical application of gene therapy is not the lack of an ideal gene, but rather the lack of a safe and efficient method to selectively deliver genes to target cells and tissues. Ultrasound-targeted microbubble destruction (UTMD), with the advantages of high safety, repetitive applicability and tissue targeting, has become a potential strategy for gene- and drug delivery. When gene-loaded microbubbles are injected, UTMD is able to enhance the transport of the gene to the targeted cells. High-amplitude oscillations of microbubbles act as cavitation nuclei which can effectively focus ultrasound energy, produce oscillations and disruptions that increase the permeability of the cell membrane and create transient pores in the cell membrane. Thereby, the efficiency of gene therapy can be significantly improved. The UTMD-mediated gene delivery system has been widely used in pre-clinical studies to enhance gene expression in a site-specific manner in a variety of organs. With reasonable application, the effects of sonoporation can be spatially and temporally controlled to improve localized tissue deposition of gene complexes for ocular gene therapy applications. In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood-retinal barrier with no significant side effects. The present review discusses the current status of gene therapy of ocular diseases as well as studies on gene therapy of ocular diseases meditated by UTMD. PMID:26151686

A Stochastic Model of Eye Lens Growth

PubMed Central

Šikić, Hrvoje; Shi, Yanrong; Lubura, Snježana; Bassnett, Steven

2015-01-01

The size and shape of the ocular lens must be controlled with precision if light is to be focused sharply on the retina. The lifelong growth of the lens depends on the production of cells in the anterior epithelium. At the lens equator, epithelial cells differentiate into fiber cells, which are added to the surface of the existing fiber cell mass, increasing its volume and area. We developed a stochastic model relating the rates of cell proliferation and death in various regions of the lens epithelium to deposition of fiber cells and lens growth. Epithelial population dynamics were modeled as a branching process with emigration and immigration between various proliferative zones. Numerical simulations were in agreement with empirical measurements and demonstrated that, operating within the strict confines of lens geometry, a stochastic growth engine can produce the smooth and precise growth necessary for lens function. PMID:25816743

Genome-Wide Association Study of Entropion Eyelid in Multiple Breeds of Sheep

USDA-ARS?s Scientific Manuscript database

Entropion is an inversion of the eyelid margin causing lashes or external hairs to rub against the ocular surface. If uncorrected, discomfort, ocular damage, increased eye infection rates, and potential blindness can occur. Entropion affects many mammalian species, can be expressed in both upper and...

Dry eye disease: pathophysiology, classification, and diagnosis.

PubMed

Perry, Henry D

2008-04-01

Dry eye disease (DED) is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, visual disturbance, and often ocular surface damage. Although recent research has made progress in elucidating DED pathophysiology, currently there are no uniform diagnostic criteria. This article discusses the normal anatomy and physiology of the lacrimal functional unit and the tear film; the pathophysiology of DED; DED etiology, classification, and risk factors; and DED diagnosis, including symptom assessment and the roles of selected diagnostic tests.

Ocular Toxicity Testing of Lunar Dust

NASA Technical Reports Server (NTRS)

Meyers, Valerie E.

2010-01-01

This slide presentation reviews the use of ocular testing to determine the toxicity of lunar dust. The OECD recommendations are reviewed. With these recommendations in mind the test methodology was to use EpiOcular, tissues derived from normal human epidermal keratinocytes, the cells of which have been differentiated on cell culture inserts to form a multi-layered structure, which closely parallels the corneal epithelium and to dose the tissue with 100 mg dust from various sources. The in-vitro study provides evidence that lunar dust is not severely corrosive or irritating, however, in vitro tests have limitations, and in vivo tests provides a more complete scenario, and information, it is recommended that in vivo tests be performed.

The Role of Medications in Causing Dry Eye

PubMed Central

Fraunfelder, Frederick T.; Sciubba, James J.; Mathers, William D.

2012-01-01

The purpose of this paper is to review the possible role of polypharmacy in causing dry eye disease (DED), reflecting the complex interactions and complications associated with the use of multiple systemic and topical ocular medications. The pharmacological, physiological, anatomical, and histological mechanisms causing dry mouth differ little from those causing dry eye. Oral polypharmacy is the most common cause of dry mouth, but has not been investigated as a cause of dry eye. Topical ocular polypharmacy has been shown to cause DED. Information on drugs that likely cause or aggravate DED and the controversial role of preservatives in topical ocular medications are examined. Systemic or topical ocular medications and preservatives used in topical ocular drugs may cause dry eye through the drug's therapeutic action, ocular surface effects, or preservatives, and the effects probably are additive. Long-term use of topical ocular medications, especially those containing preservatives such as BAK, may play an important role in DED and the role of polypharmacy needs further study. We review possible ways to decrease the risk of medication-related dry eye. PMID:23050121

Cytoprotective effect of lacritin on human corneal epithelial cells exposed to benzalkonium chloride in vitro

PubMed Central

Feng, Mary M.; Baryla, Julia; Liu, Hong; Laurie, Gordon W.; McKown, Robert L.; Ashki, Negin; Bhayana, Dinesh

2015-01-01

Purpose Benzalkonium chloride (BAK) is the most commonly found preservative in eye drops, and has been shown to cause ocular surface inflammation and toxicity. Lacritin is a human tear glycoprotein secreted from the lacrimal glands that has been found to be cytoprotective. This study was designed to determine if the presence of lacritin confers protection to a cultured human corneal epithelial (HCE) cell line, CRL-11515, and primary HCE cells after exposure to the ocular preservative agent BAK. Materials and Methods Recombinant human lacritin was cloned into intein fusion vectors, expressed in E. coli, and purified on chitin beads and DEAE Sepharose. Metabolic curves were established using the MTT assay after exposure of subconfluent CRL-11515 cells to BAK or lacritin. Western blot analysis of lipidated LC3 (LC3-II) provided a measure of autophagy in CRL-11515 cells exposed to lacritin and/or BAK. Results BAK reduced CRL-11515 cellular metabolic activity in a time and dose dependent manner. BAK-induced cellular stress was evident by elevated autophagy that increased with rising concentrations of BAK compared to control (P < 0.05). Lacritin increased HCE cell proliferation at an optimal dose of 1 nM. Preconditioning HCE cells with 1 nM lacritin for 24 hours prior to BAK exposure significantly dampened levels of LC3-II (P < 0.05) and promoted a significant increase in cellular metabolic activity (P < 0.01) compared to BAK alone. Conclusions These results suggest lacritin protects cultured HCE cells stressed with BAK. Lacritin may have the potential to be used as a topical adjunctive therapy in eyes chronically exposed to BAK. PMID:24401093

Cytoprotective effect of lacritin on human corneal epithelial cells exposed to benzalkonium chloride in vitro.

PubMed

Feng, Mary M; Baryla, Julia; Liu, Hong; Laurie, Gordon W; McKown, Robert L; Ashki, Negin; Bhayana, Dinesh; Hutnik, Cindy M L

2014-06-01

Benzalkonium chloride (BAK) is the most commonly found preservative in eye drops, and has been shown to cause ocular surface inflammation and toxicity. Lacritin is a human tear glycoprotein secreted from the lacrimal glands that has been found to be cytoprotective. This study was designed to determine if the presence of lacritin confers protection to a cultured human corneal epithelial (HCE) cell line, CRL-11515, and primary HCE cells after exposure to the ocular preservative agent BAK. Recombinant human lacritin was cloned into intein fusion vectors, expressed in E. coli, and purified on chitin beads and DEAE Sepharose. Metabolic curves were established using the MTT assay after exposure of sub-confluent CRL-11515 cells to BAK or lacritin. Western blot analysis of lipidated LC3 (LC3-II) provided a measure of autophagy in CRL-11515 cells exposed to lacritin and/or BAK. BAK reduced CRL-11515 cellular metabolic activity in a time- and dose-dependent manner. BAK-induced cellular stress was evident by elevated autophagy that increased with rising concentrations of BAK compared to control (p < 0.05). Lacritin increased HCE cell proliferation at an optimal dose of 1 nM. Preconditioning HCE cells with 1 nM lacritin for 24 h prior to BAK exposure significantly dampened levels of LC3-II (p < 0.05) and promoted a significant increase in cellular metabolic activity (p < 0.01) compared to BAK alone. These results suggest lacritin protects cultured HCE cells stressed with BAK. Lacritin may have the potential to be used as a topical adjunctive therapy in eyes chronically exposed to BAK.

In Vitro Effects of Preserved and Unpreserved Anti-Allergic Drugs on Human Corneal Epithelial Cells

PubMed Central

Calvo, Patricia; Ropero, Inés; Pintor, Jesús

2014-01-01

Abstract Purpose: Treatment with topical eye drops for long-standing ocular diseases like allergy can induce detrimental side effects. The purpose of this study was to investigate in vitro cytotoxicity of commercially preserved and unpreserved anti-allergic eye drops on the viability and barrier function of monolayer and stratified human corneal-limbal epithelial cells. Methods: Cells were treated with unpreserved ketotifen solution, benzalkonium chloride (BAC)-containing anti-allergic drugs (ketotifen, olopatadine, levocabastine) as well as BAC alone. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine cell viability. Effects of compounds on barrier function were analyzed measuring transepithelial electrical resistance (TEER) to determine paracellular permeability and rose bengal assays to evaluate transcellular barrier formation. Results: The BAC-preserved anti-allergic formulations and BAC alone significantly reduced cell viability, monolayer cultures being more sensitive to damage by these solutions. Unpreserved ketotifen induced the least diminution in cell viability. The extent of decrease of cell viability was clearly dependent of BAC presence, but it was also affected by the different types of drugs when the concentration of BAC was low and the short time of exposure. Treatment with BAC-containing anti-allergic drugs and BAC alone resulted in increased paracellular permeability and loss of transcellular barrier function as indicated by TEER measurement and rose bengal assays. Conclusions: The presence of the preservative BAC in anti-allergic eye drop formulations contributes importantly to the cytotoxic effects induced by these compounds. Stratified cell cultures seem to be a more relevant model for toxicity evaluation induced on the ocular surface epithelia than monolayer cultures. PMID:25100331

Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics.

PubMed

Kulkarni, Bina B; Tighe, Patrick J; Mohammed, Imran; Yeung, Aaron M; Powe, Desmond G; Hopkinson, Andrew; Shanmuganathan, Vijay A; Dua, Harminder S

2010-09-29

The Limbal epithelial crypt (LEC) is a solid cord of cells, approximately 120 microns long. It arises from the undersurface of interpalisade rete ridges of the limbal palisades of Vogt and extends deeper into the limbal stroma parallel or perpendicular to the palisade. There are up to 6 or 7 such LEC, variably distributed along the limbus in each human eye. Morphological and immunohistochemical studies on the limbal epithelial crypt (LEC) have demonstrated the presence of limbal stem cells in this region. The purpose of this microarray study was to characterise the transcriptional profile of the LEC and compare with other ocular surface epithelial regions to support our hypothesis that LEC preferentially harbours stem cells (SC). LEC was found to be enriched for SC related Gene Ontology (GO) terms including those identified in quiescent adult SC, however similar to cornea, limbus had significant GO terms related to proliferating SC, transient amplifying cells (TAC) and differentiated cells (DC). LEC and limbus were metabolically dormant with low protein synthesis and downregulated cell cycling. Cornea had upregulated genes for cell cycling and self renewal such as FZD7, BTG1, CCNG, and STAT3 which were identified from other SC populations. Upregulated gene expression for growth factors, cytokines, WNT, Notch, TGF-Beta pathways involved in cell proliferation and differentiation were noted in cornea. LEC had highest number of expressed sequence tags (ESTs), downregulated and unknown genes, compared to other regions. Genes expressed in LEC such as CDH1, SERPINF1, LEF1, FRZB1, KRT19, SOD2, EGR1 are known to be involved in SC maintenance. Genes of interest, in LEC belonging to the category of cell adhesion molecules, WNT and Notch signalling pathway were validated with real-time PCR and immunofluorescence. Our transcriptional profiling study identifies the LEC as a preferential site for limbal SC with some characteristics suggesting that it could function as a 'SC niche' supporting quiescent SC. It also strengthens the evidence for the presence of "transient cells" in the corneal epithelium. These cells are immediate progeny of SC with self-renewal capacity and could be responsible for maintaining epithelial turn over in normal healthy conditions of the ocular surface (OS). The limbus has mixed population of differentiated and undifferentiated cells.

Impact of magnetic field strength and receiver coil in ocular MRI: a phantom and patient study.

PubMed

Erb-Eigner, K; Warmuth, C; Taupitz, M; Willerding, G; Bertelmann, E; Asbach, P

2013-09-01

Generally, high-resolution MRI of the eye is performed with small loop surface coils. The purpose of this phantom and patient study was to investigate the influence of magnetic field strength and receiver coils on image quality in ocular MRI. The eyeball and the complex geometry of the facial bone were simulated by a skull phantom with swine eyes. MR images were acquired with two small loop surface coils with diameters of 4 cm and 7 cm and with a multi-channel head coil at 1.5 and 3 Tesla, respectively. Furthermore, MRI of the eye was performed prospectively in 20 patients at 1.5 Tesla (7 cm loop surface coil) and 3 Tesla (head coil). These images were analysed qualitatively and quantitatively and statistical significance was tested using the Wilcoxon-signed-rank test (a p-value of less than 0.05 was considered to indicate statistical significance). The analysis of the phantom images yielded the highest mean signal-to-noise ratio (SNR) at 3 Tesla with the use of the 4 cm loop surface coil. In the phantom experiment as well as in the patient studies the SNR was higher at 1.5 Tesla by applying the 7 cm surface coil than at 3 Tesla by applying the head coil. Concerning the delineation of anatomic structures no statistically significant differences were found. Our results show that the influence of small loop surface coils on image quality (expressed in SNR) in ocular MRI is higher than the influence of the magnetic field strength. The similar visibility of detailed anatomy leads to the conclusion that the image quality of ocular MRI at 3 Tesla remains acceptable by applying the head coil as a receiver coil. © Georg Thieme Verlag KG Stuttgart · New York.

Sutureless Fixation of Amniotic Membrane for Therapy of Ocular Surface Disorders

PubMed Central

Kotomin, Ilya; Valtink, Monika; Hofmann, Kai; Frenzel, Annika; Morawietz, Henning; Werner, Carsten; Funk, Richard H. W.; Engelmann, Katrin

2015-01-01

Amniotic membrane is applied to the diseased ocular surface to stimulate wound healing and tissue repair, because it releases supportive growth factors and cytokines. These effects fade within about a week after application, necessitating repeated application. Generally, amniotic membrane is fixed with sutures to the ocular surface, but surgical intervention at the inflamed or diseased site can be detrimental. Therefore, we have developed a system for the mounting of amniotic membrane between two rings for application to a diseased ocular surface without surgical intervention (sutureless amniotic membrane transplantation). With this system, AmnioClip, amniotic membrane can be applied like a large contact lens. First prototypes were tested in an experiment on oneself for wearing comfort. The final system was tested on 7 patients in a pilot study. A possible influence of the ring system on the biological effects of amniotic membrane was analyzed by histochemistry and by analyzing the expression of vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF 2) and pigment epithelium-derived factor (PEDF) from amniotic membranes before and after therapeutic application. The final product, AmnioClip, showed good tolerance and did not impair the biological effects of amniotic membrane. VEGF-A and PEDF mRNA was expressed in amniotic membrane after storage and mounting before transplantation, but was undetectable after a 7-day application period. Consequently, transplantation of amniotic membranes with AmnioClip provides a sutureless and hence improved therapeutic strategy for corneal surface disorders. Trial Registration ClinicalTrials.gov NCT02168790 PMID:25955359

Chronic dry eye in photorefractive keratectomy and laser in situ keratomileusis: Manifestations, incidence, and predictive factors.

PubMed

Bower, Kraig S; Sia, Rose K; Ryan, Denise S; Mines, Michael J; Dartt, Darlene A

2015-12-01

To evaluate dry-eye manifestations after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) and determine the incidence and predictive factors of chronic dry eye using a set of dry-eye criteria. Walter Reed Army Medical Center, Washington, DC, USA. Prospective, non-randomized clinical study. Dry-eye evaluation was performed before and after surgery. Main outcome measures included dry-eye manifestations, incidence, and predictive factors of chronic dry eye. This study comprised 143 active-duty U.S. Army personnel, ages 29.9 ± 5.2 years, with myopia or myopic astigmatism (manifest spherical equivalent -3.83 ± 1.96 diopters) having PRK or LASIK. Schirmer scores, corneal sensitivity, ocular surface staining, surface regularity index, and responses to dry-eye questionnaire significantly changed over time after PRK. After LASIK, significant changes were observed in tear breakup time, corneal sensitivity, ocular surface staining, and responses to questionnaire. Twelve months postoperatively, 5.0% of PRK and 0.8% of LASIK participants developed chronic dry eye. Regression analysis showed that pre-operatively lower Schirmer score will significantly influence development of chronic dry eye after PRK, whereas preoperatively, lower Schirmer score or higher ocular surface staining score will significantly influence the occurrence of chronic dry eye after LASIK. Chronic dry eye was uncommon after PRK and LASIK. Ocular surface and tear-film characteristics during pre-operative examination might help to predict chronic dry-eye development in PRK and LASIK. The authors have no financial interest in any product, drug, instrument, or equipment discussed in this manuscript. Copyright © 2015 ASCRS and ESCRS. All rights reserved.

Influenza Virus Respiratory Infection and Transmission Following Ocular Inoculation in Ferrets

PubMed Central

Belser, Jessica A.; Gustin, Kortney M.; Maines, Taronna R.; Pantin-Jackwood, Mary J.; Katz, Jacqueline M.; Tumpey, Terrence M.

2012-01-01

While influenza viruses are a common respiratory pathogen, sporadic reports of conjunctivitis following human infection demonstrates the ability of this virus to cause disease outside of the respiratory tract. The ocular surface represents both a potential site of virus replication and a portal of entry for establishment of a respiratory infection. However, the properties which govern ocular tropism of influenza viruses, the mechanisms of virus spread from ocular to respiratory tissue, and the potential differences in respiratory disease initiated from different exposure routes are poorly understood. Here, we established a ferret model of ocular inoculation to explore the development of virus pathogenicity and transmissibility following influenza virus exposure by the ocular route. We found that multiple subtypes of human and avian influenza viruses mounted a productive virus infection in the upper respiratory tract of ferrets following ocular inoculation, and were additionally detected in ocular tissue during the acute phase of infection. H5N1 viruses maintained their ability for systemic spread and lethal infection following inoculation by the ocular route. Replication-independent deposition of virus inoculum from ocular to respiratory tissue was limited to the nares and upper trachea, unlike traditional intranasal inoculation which results in virus deposition in both upper and lower respiratory tract tissues. Despite high titers of replicating transmissible seasonal viruses in the upper respiratory tract of ferrets inoculated by the ocular route, virus transmissibility to naïve contacts by respiratory droplets was reduced following ocular inoculation. These data improve our understanding of the mechanisms of virus spread following ocular exposure and highlight differences in the establishment of respiratory disease and virus transmissibility following use of different inoculation volumes and routes. PMID:22396651

Feasibility of quantitatively diagnosing cornea infection using Raman spectroscopy (Conference Presentation)

NASA Astrophysics Data System (ADS)

Bai, Yanru; Chen, Keren; Mishra, Arti; Beuerman, Roger; Liu, Quan

2017-02-01

Ocular infection is a serious eye disease that could lead to blindness without prompt and proper treatment. In pathology, ocular infection is caused by microorganisms such as bacteria, fungi or viruses. The essential prerequisite for the optimal treatment of ocular infection is to identify the microorganism causing infection early as each type of microorganism requires a different therapeutic approach. The clinical procedure for identifying the microorganism species causing ocular infection includes Gram staining (for bacteria)/microscopy (for fungi) and the culture of corneal surface scraping, or aqueous and vitreous smear samples taken from the surface of infected eyes. The culture procedure is labor intensive and expensive. Moreover, culturing is time consuming, which usually takes a few days or even weeks. Such a long delay in diagnosis could result in the exacerbation of patients' symptoms, the missing of the optimal time frame for initiating treatment and subsequently the rising cost for disease management. Raman spectroscopy has been shown highly effective for non-invasive identification of both fungi and bacteria qualitatively. In this study, we investigate the feasibility of identifying the microorganisms of ocular infection and quantifying the concentrations using Raman spectroscopy by measuring not only gram negative and gram positive bacteria but also infected cornea. By applying a modified orthogonal projection approach, the relative concentration of each bacteria species could be quantified. Our results indicate the great potential of Raman spectroscopy as an alternative tool for non-invasive diagnosis of ocular infection and could play a significantly role in future ophthalmology.

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

PubMed

Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D; Mitra, Ashim K

2017-02-28

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Prevalencia de síntomas de enfermedad de la superficie ocular en pacientes que acuden a consulta oftalmológica.

PubMed

Garza-León, Manuel; Hernández-Quintela, Everardo; Cámara-Castillo, Héctor G; Parra-Collin, Paola de la; Covarrubias-Espinosa, Paola; Sánchez-Huerta, Valeria; Castillo-Ruiz, Alejandro Del; Rodríguez-Sixtos, Fernando; Pacheco-Patrón, Jorge; Ochoa-Tabares, Juan Carlos; Soto-Ortiz, Karina; Hernández-Olguin, Karen

2017-01-01

To determine the prevalence of symptoms of ocular surface disease (OSDI) surface disease and its relationship with associated risk factors in patients of ophthalmic practices using OSDI questionnaire. A cross-sectional survey was conducted Between September and December 2014 to assess the prevalence and risk factors for OSDI. The OSDI average value was 40.46 ± 23.62 points, with 86.4% of patients (1967) having a OSDI score higher than 12 points. Women had OSDI symptoms more frequently than men (odds ratio: 1.17; 95% confidence interval: 1.08-1.28) and higher OSDI score (42.12 ± 24.03 vs. 38.01 ± 22.81 points). Patients without disease were younger than the patients with severe disease (45.30 ± 18.32 vs. 50.62 ± 18.86). Ophthalmological patients have a prevalence of 80.4% of OSDI. Female and older age was associated with ocular surface disease. Copyright: © 2017 SecretarÍa de Salud

Efficacy and safety of two new formulations of artificial tears in subjects with dry eye disease: a 3-month, multicenter, active-controlled, randomized trial

PubMed Central

Simmons, Peter A; Liu, Haixia; Carlisle-Wilcox, Cindy; Vehige, Joseph G

2015-01-01

Purpose To evaluate and compare the efficacy and safety of two investigational artificial tear formulations (CHO-1 and CHO-2) containing carmellose sodium, hyaluronic acid at different concentrations, and osmoprotectants, with a standard carmellose sodium-containing formulation (Refresh Tears [RT]) in the treatment of dry eye disease. Subjects and methods In this 3-month, double-masked, multicenter study, subjects (n=305) were randomized 1:1:1 to receive CHO-1, CHO-2, or RT, used as needed but at least twice daily. The primary endpoint was change in ocular surface disease index (OSDI) score from baseline to day 90. Other key outcomes included symptoms evaluated on a visual analog scale, corneal and conjunctival staining, and adverse events. Results OSDI scores and dry eye symptoms showed a rapid and sustained reduction from baseline in each group. Both CHO-1 and CHO-2 met the primary efficacy endpoint of noninferiority to RT in day 90 OSDI score change from baseline. OSDI ocular symptoms subscale improved more with CHO-1 than CHO-2 (P=0.048). In subjects with clinically relevant baseline ocular surface staining (>14 total score of a maximum of 55), day 90 improvements were greater with CHO-1 and CHO-2 than RT (P≤0.044). Day 90 improvements in OSDI ocular symptoms subscale scores were also greater with CHO-1 than RT (P<0.007) in subjects with clinically relevant ocular staining. All treatments were well tolerated. Conclusion Both combination artificial tear formulations were efficacious and well tolerated in subjects with dry eye. CHO-1 demonstrated the best performance in improving ocular symptoms and reducing ocular staining in this heterogeneous study population. PMID:25931807

The Endocytic Recycling Regulatory Protein EHD1 Is Required for Ocular Lens Development

PubMed Central

Arya, Priyanka; Rainey, Mark A.; Bhattacharyya, Sohinee; Mohapatra, Bhopal; George, Manju; Kuracha, Murali R; Storck, Matthew D.; Band, Vimla; Govindarajan, Venkatesh; Band, Hamid

2015-01-01

The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis. PMID:26455409

Regulation of ocular surface inflammation by prostaglandin E receptor subtype EP3.

PubMed

Ueta, Mayumi

2010-11-01

We first investigated whether the prostaglandin (PG) E2-PGE receptor subtype EP3 axis regulates the development of murine experimental allergic conjunctivitis because it has been reported that this pathway negatively regulates allergic reactions in a murine allergic asthma model. We observed that EP3 is constitutively expressed in mice conjunctival epithelium. EP3 knockout mice demonstrated significantly increased eosinophil infiltration in conjunctiva after ragweed challenge compared with wild-type mice. Consistently, significantly higher expression of eotaxin-1 messenger RNA was observed in Ptger3-/- mice. Conversely, treatment of wild-type mice with an EP3-selective agonist significantly decreased eosinophil infiltration, which was blunted in Ptger3-/- mice. Expression of cyclooxygenase-2 and PGE synthases was upregulated and PGE2 content increased in the eyelids after ragweed challenge. These data suggest that PGE2 acts on EP3 in the conjunctival epithelium and downregulates the progression of experimental allergic conjunctivitis. We next examined and compared the expression of EP3 in human conjunctival epithelium in various ocular surface diseases. Human conjunctival epithelium expressed EP3-specific messenger RNA and EP3 protein. Although we could clearly find positive signals in the conjunctival epithelium from patients with noninflammatory ocular surface diseases such as conjunctivochalasis and pterygium, we could not find positive signals in that from those with inflammatory disorders such as Stevens-Johnson syndrome and ocular cicatricial pemphigoid. Likewise, expression of the PGE receptor subtype EP4 was clearly found in the conjunctival epithelium from patients with conjunctivochalasis and pterygium but not from patients with Stevens-Johnson syndrome and ocular cicatricial pemphigoid.

Ocular surface changes following oral anticholinergic use for overactive bladder.

PubMed

Sekeroglu, Mehmet Ali; Hekimoglu, Emre; Tasci, Yasemin; Dolen, Ismail; Arslan, Umut

2016-09-01

To investigate the effect of oral solifenacin succinate on Schirmer I test results, tear break-up time (TBUT) and Ocular Surface Disease Index (OSDI) scores in overactive bladder (OAB) patients and to compare these results with those of healthy control subjects. The female OAB patients who were prescribed oral solifenacin succinate 5 mg/day (Group I, N = 80) and age-matched healthy female subjects (Group II, N = 40) were recruited for the study and underwent ophthalmological examination prior to oral treatment and after 4 weeks. They completed the OSDI questionnaire and underwent ocular surface tests including Schirmer I test and TBUT. The statistical analysis of the Schirmer I test and TBUT revealed no significant difference between the baseline and 4th week values in both groups (Group I, p = 0.506 and p = 0.070 consecutively) (Group II, p = 0.810 and p = 0.823 consecutively). OSDI scores were found to be significantly increased in group I (21.8 ± 4.2 vs 23.1 ± 4.6, p = 0.020) and remained unchanged in group II (20.5 ± 7.0 vs 20.7 ± 7.0, p = 0.805). Short-term solifenacin succinate treatment has no effect on the Schirmer I test results and TBUT, but ocular surface symptoms appeared to be exacerbated in respect with increased OSDI scores. However, the clinical significance needs to be further evaluated with larger studies.

Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and Preservatives.

PubMed

Ramli, Norlina; Supramaniam, Gowri; Samsudin, Amir; Juana, Azida; Zahari, Mimiwati; Choo, May May

2015-09-01

To evaluate the prevalence of ocular surface disease (OSD) in glaucoma and nonglaucoma subjects using different clinical tests and to determine the effect of number of antiglaucoma medications and preservatives on OSD. This is a cross-sectional, case-comparison study at the Eye Clinic of the University of Malaya Medical Centre, Malaysia, between June 2012 and January 2013. Glaucoma subjects (n = 105) using topical antiglaucoma medications were compared with control subjects (n = 102) who were not on any topical medications. The presence of OSD was assessed using the tear film breakup time (TBUT) test, corneal staining, Schirmer test, and Ocular Surface Disease Index (OSDI) questionnaire grading. The prevalence of OSD varied from 37 to 91% in the glaucoma group, depending on the type of clinical test. More subjects in the glaucoma group had corneal staining (63% vs. 36%, p = 0.004), abnormal Schirmer tests (39% vs. 25%, p = 0.049), and moderate OSDI symptoms (17% vs. 7%, p = 0.028). The percentage with abnormal TBUT increased with higher numbers of topical medications and was high with both benzalkonium chloride-containing and preservative-free eye drops (90% and 94%, respectively, both p < 0.001). Benzalkonium chloride was associated with a nearly three times higher odds ratio of showing abnormal OSDI. Ocular surface disease is common in those using topical antiglaucoma medications. Abnormal TBUT is associated with increasing number of eye drops and benzalkonium chloride-containing eye drops, although this also occurs with the use of preservative-free eye drops.

Ocular surface infections in northeastern state of malaysia: a 10-year review of bacterial isolates and antimicrobial susceptibility.

PubMed

Rahman, Zaidah A; Harun, Azian; Hasan, Habsah; Mohamed, Zeehaida; Noor, Siti S Md; Deris, Zakuan Z; Ismail, Nabilah; Hassan, Asma S; Ahmad, Fadzhilah; Yaakub, Azhany

2013-09-01

Ocular surface infections that include infections of conjunctiva, adnexa, and cornea have the potential risk of causing blindness within a given population. Empirical antibiotic therapy is usually initiated based on epidemiological data of common causative agents. Thus, the aims of this study were to determine the bacterial agents and their susceptibility patterns of isolates from ocular surface specimens in our hospital. This is a retrospective analysis and records of bacterial isolates from ocular surface specimens in Hospital Universiti Sains Malaysia from January 2001 to December 2010 were examined. Specimens were processed according to standard laboratory procedures. Antimicrobial susceptibility testing was conducted based on Clinical and Laboratory Standards Institute recommendations. Only single, nonrepetitive isolates were included in the analysis. A total of 1,267 isolates were obtained during the study period, which comprised Staphylococcus aureus (n = 299, 23.6%), Pseudomonas aeruginosa (n = 194, 15.3%), Streptococcus pneumoniae (n = 108, 8.5%), Haemophilus influenzae (n = 100, 7.9%), Haemophilus parainfluenzae (n = 84, 6.6%), and Enterobacter spp. (n = 81, 6.4%). Fungi contributed to 4.4% of the total isolates. The antimicrobial susceptibility testing demonstrated that gram-positive bacteria were generally resistant to gentamicin (19%-57%), whereas gram-negative bacteria were resistant to chloramphenicol (27%-58%). Based on the above results, knowledge of the initial Gram stain findings is imperative before the commencement of empirical antibiotic therapy. Therefore, a simple Gram staining for all eye specimens is highly recommended.

Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aslan, Mutay, E-mail: mutayaslan@akdeniz.edu.tr; Basaranlar, Goksun; Unal, Mustafa

Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK,more » CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress. - Highlights: • Inhibition of N-SMase decreases NOS2 levels in ocular hypertension. • Inhibition of N-SMase decreases protein nitration in ocular hypertension. • Inhibition of N-SMase decreases caspase activation in ocular hypertension. • Inhibition of N-SMase decreases apoptosis in ocular hypertension.« less

Two-photon excited fluorescence microscopy application for ex vivo investigation of ocular fundus samples

NASA Astrophysics Data System (ADS)

Peters, Sven; Hammer, Martin; Schweitzer, Dietrich

2011-07-01

Two-photon excited fluorescence (TPEF) imaging of ocular tissue has recently become a promising tool in ophthalmology for diagnostic and research purposes. The feasibility and the advantages of TPEF imaging, namely deeper tissue penetration and improved high-resolution imaging of microstructures, have been demonstrated lately using human ocular samples. The autofluorescence properties of endogenous fluorophores in ocular fundus tissue are well known from spectrophotometric analysis. But fluorophores, especially when it comes to fluorescence lifetime, typically display a dependence of their fluorescence properties on local environmental parameters. Hence, a more detailed investigation of ocular fundus autofluorescence ideally in vivo is of utmost interest. The aim of this study is to determine space-resolved the stationary and time-resolved fluorescence properties of endogenous fluorophores in ex vivo porcine ocular fundus samples by means of two-photon excited fluorescence spectrum and lifetime imaging microscopy (FSIM/FLIM). By our first results, we characterized the autofluorescence of individual anatomical structures of porcine retina samples excited at 760 nm. The fluorescence properties of almost all investigated retinal layers are relatively homogenous. But as previously unknown, ganglion cell bodies show a significantly shorter fluorescence lifetime compared to the adjacent mueller cells. Since all retinal layers exhibit bi-exponential autofluorescence decays, we were able to achieve a more precise characterization of fluorescence properties of endogenous fluorophores compared to a present in vivo FLIM approach by confocal scanning laser ophthalmoscope (cSLO).

Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Cornea and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect against Ocular Herpes Challenge.

PubMed

Khan, Arif A; Srivastava, Ruchi; Vahed, Hawa; Roy, Soumyabrata; Walia, Sager S; Kim, Grace J; Fouladi, Mona A; Yamada, Taikun; Ly, Vincent T; Lam, Cynthia; Lou, Anthony; Nguyen, Vivianna; Boldbaatar, Undariya; Geertsema, Roger; Fraser, Nigel W; BenMohamed, Lbachir

2018-06-13

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that infects the cornea causing potentially blinding herpetic disease. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull vaccine was tested in Human Leukocyte Antigen- (HLA-) transgenic rabbit model of ocular herpes (HLA Tg rabbit). Three asymptomatic (ASYMP) peptide epitopes were selected from the HSV-1 membrane glycoprotein C (UL44 400-408 ), the DNA replication binding helicase (UL9 196-204 ), and the tegument protein (UL25 572-580 ), all preferentially recognized by CD8 + T cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were immunized with a mixture of these three ASYMP CD8 + T cell peptide epitopes (UL44 400-408 , UL9 196-204 and UL25 572-580 ), delivered subcutaneously with CpG 2007 adjuvant (prime). Fifteen days later, half of the rabbits received a topical ocular treatment with a recombinant neurotropic AAV8 vector, expressing the T cell-attracting CXCL10 chemokine (pull). The frequency, function of HSV-specific CD8 + T cells induced by the prime/pull vaccine were assessed in peripheral blood, cornea, and trigeminal ganglia (TG). Compared to peptides alone, the peptides/CXCL10 prime/pull vaccine generated frequent polyfunctional gamma interferon-positive (IFN-γ + ) CD107 + CD8 + T cells that infiltrated both the cornea and TG. CD8 + T cells mobilization into cornea and TG of prime/pull- vaccinated rabbits was associated with a significant reduction in corneal herpes infection and disease following an ocular HSV-1 challenge (McKrae). These findings draw attention to the novel prime/pull vaccine strategy to mobilize anti-viral CD8 + T cells into tissues protecting them against herpes infection and disease. IMPORTANCE There is an urgent need for a vaccine against widespread herpes simplex virus infections. The present study demonstrates that immunization of HLA transgenic rabbits with a peptide/CXCL10 prime/pull vaccine triggered mobilization of HSV-specific CD8 + T cells locally in the cornea and TG, the sites of acute and latent herpes infections. Mobilization of antiviral CD8 + T cells into cornea and TG of rabbits that received the prime/pull vaccine was associated with protection against ocular herpes infection and disease following an ocular HSV-1 challenge. These results highlight the importance of the prime/pull vaccine strategy to bolster the number and function of protective CD8 + T cells within infected tissues. Copyright © 2018 American Society for Microbiology.

Ocular sensitization of mice by live (but not irradiated) Chlamydia trachomatis serovar A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colley, D.G.; Goodman, T.G.; Barsoum, I.S.

1986-10-01

Ocular exposure of mice to live elementary bodies of Chlamydia trachomatis serovar A results in immunological sensitization of the mice. This reactivity is manifested by the development of early (5 h) and delayed-type (24 h) dermal reactivity and serovar-specific antibody formation against either live or irradiated (100 kilorads) elementary bodies. Parallel ocular exposure of mice to irradiated elementary bodies does not result in this sensitization. The early and late dermal immune responses induced by ocular exposure to live organisms can be transferred to unexposed mice by serum and lymphoid cell transfers, respectively. It appears that successful murine ocular sensitization bymore » human C. trachomatis serovar A elementary bodies is an ability manifested by live organisms and not by inactivated but antigenic organisms.« less

INS365 suppresses loss of corneal epithelial integrity by secretion of mucin-like glycoprotein in a rabbit short-term dry eye model.

PubMed

Fujihara, Tsutomu; Murakami, Tadahiro; Nagano, Takashi; Nakamura, Masatsugu; Nakata, Katsuhiko

2002-08-01

P2Y2 receptor agonists, like UTP and ATP, stimulate mucin secretion from goblet cells in vitro. Therefore, mucin stimulants could be good candidates for the treatment of dry eye syndrome because mucin increases the tear film stability and protects against desiccation of ocular surface. INS365 is a more stable P2Y2 receptor agonist than UTP. In the present study, we evaluated, in normal rabbit eyes, its effectiveness to release mucin from goblet cells and to protect the corneal damage induced by desiccation. For mucin secretion, impression cytology was performed following the instillation of INS365 solution or saline into the conjunctival sac. The specimens were stained with periodic acid and Schiff (PAS) reagent, and then the staining area was calculated using computer software. INS365 dose-dependently decreased the PAS staining area of conjunctival goblet cells from 2 to 15 min post-application. Furthermore, we utilized the rabbit short-term dry eye model to evaluate if INS365 eyedrops could protect against any of the damage produced by blockage of blinking with ocular speculum. INS365 significantly suppressed corneal damage at concentrations of more than 0.1% w/v. These results suggest that this P2Y2 agonist is a good candidate for the treatment of dry eye disease.

Association of a NOD2 Gene Polymorphism and T-Helper 17 Cells With Presumed Ocular Toxoplasmosis

PubMed Central

Dutra, Míriam S.; Béla, Samantha R.; Peixoto-Rangel, Alba L.; Fakiola, Michaela; Cruz, Ariane G.; Gazzinelli, Andrea; Quites, Humberto F.; Bahia-Oliveira, Lilian M. G.; Peixe, Ricardo G.; Campos, Wesley R.; Higino-Rocha, Anna C.; Miller, Nancy E.; Blackwell, Jenefer M.; Antonelli, Lis R.; Gazzinelli, Ricardo T.

2013-01-01

Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon γ (IFN-γ) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4+CD45RO+T-bet−IFN-γ− T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4+ T lymphocytes and might contribute to the development of ocular toxoplasmosis. PMID:23100559

Association of a NOD2 gene polymorphism and T-helper 17 cells with presumed ocular toxoplasmosis.

PubMed

Dutra, Míriam S; Béla, Samantha R; Peixoto-Rangel, Alba L; Fakiola, Michaela; Cruz, Ariane G; Gazzinelli, Andrea; Quites, Humberto F; Bahia-Oliveira, Lilian M G; Peixe, Ricardo G; Campos, Wesley R; Higino-Rocha, Anna C; Miller, Nancy E; Blackwell, Jenefer M; Antonelli, Lis R; Gazzinelli, Ricardo T

2013-01-01

Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon γ (IFN-γ) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4(+)CD45RO(+)T-bet(-)IFN-γ(-) T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4(+) T lymphocytes and might contribute to the development of ocular toxoplasmosis.

Ocular Adverse Events Associated with Antibody–Drug Conjugates in Human Clinical Trials

PubMed Central

Miller, Paul E.; Mannis, Mark J.

2015-01-01

Abstract This article reviews ocular adverse events (AEs) reported in association with administration of antibody–drug conjugates (ADCs) in human clinical trials. References reporting ocular toxicity or AEs associated with ADCs were collected using online publication searches. Articles, abstracts, or citations were included if they cited ocular toxicities or vision-impairing AEs with a confirmed or suspected association with ADC administration. Twenty-two references were found citing ocular or vision-impairing AEs in association with ADC administration. All references reported use of ADCs in human clinical trials for treatment of various malignancies. The molecular target and cytotoxic agent varied depending on the ADC used. Ocular AEs affected a diversity of ocular tissues. The most commonly reported AEs involved the ocular surface and included blurred vision, dry eye, and corneal abnormalities (including microcystic corneal disease). Most ocular AEs were not severe (≤ grade 2) or dose limiting. Clinical outcomes were not consistently reported, but when specified, most AEs improved or resolved with cessation of treatment or with ameliorative therapy. A diverse range of ocular AEs are reported in association with administration of ADCs for the treatment of cancer. The toxicologic mechanism(s) and pathogenesis of such events are not well understood, but most are mild in severity and reversible. Drug development and medical professionals should be aware of the clinical features of these events to facilitate early recognition and intervention in the assessment of preclinical development programs and in human clinical trials. PMID:26539624

Meibomian gland dysfunction and ocular discomfort in video display terminal workers.

PubMed

Fenga, C; Aragona, P; Cacciola, A; Spinella, R; Di Nola, C; Ferreri, F; Rania, L

2008-01-01

Meibomian gland dysfunction (MGD) is one of the most common ocular disorders encountered in clinical practice. The clinical manifestations of MGD are related to the changes in the tear film and ocular surface with symptoms of ocular discomfort. In recent years, many surveys have evaluated symptoms associated with the use of Video Display Terminals (VDT), and VDT use is recognized as a risk factor for eye discomfort. The aim of the present study was to determine if the presence of MGD contributes to the signs and symptoms of ocular discomfort during the use of VDT. In course of a routine health surveillance programme, a group of 70 subjects fulfilled the inclusion criteria and responded to a questionnaire about symptoms of ocular discomfort. The following ocular tests were performed: tear break-up time, fluorescein corneal stain, and basal tear secretion test. A total of 52 subjects out of 70 (74.3%) had MGD. A statistically significant correlation between the symptoms of ocular discomfort and hours spent on VDT work was observed in the total population (r=0.358; P=0.002; 95% CI 0.13-0.54) and in the group of subjects with MGD (r=0.365; P=0.009; 95% CI 0.103-0.58). Such correlation was not shown in subjects without MGD. The high prevalence of MGD among the subjects with symptoms of ocular discomfort suggests that this diagnosis should be considered when occupational health practitioners encounter ocular complaints among VDT operators. It appears that MGD can contribute to the development of ocular discomfort in VDT operators.

[Novel current and future therapy options for treatment of dry eye disease].

PubMed

Messmer, E M

2018-02-01

Dry eye disease was redefined by the dry eye workshop (DEWS II) in May 2017. According to the new definition "dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms". The current definition encompasses etiological factors, such as instability and hyperosmolarity of the tear film, ocular surface inflammation and damage as well as a new aspect compared to the former definition, neurosensory abnormalities. Recent and future therapeutic options for dry eye focus on treatment of the aforementioned pathogenetic events. New tear substitutes, medications and devices to stimulate tear production, innovative anti-inflammatory treatment, medications to influence corneal innervation and new methods for treatment of Meibomian gland dysfunction are already available or will be available in the near future.

Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

PubMed

Agustoni, Francesco; Platania, Marco; Vitali, Milena; Zilembo, Nicoletta; Haspinger, Eva; Sinno, Valentina; Gallucci, Rosaria; de Braud, Filippo; Garassino, Marina Chiara

2014-02-01

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, "hand-foot syndrome", and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1-3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ocular manifestations of rheumatoid arthritis and their correlation with anti-cyclic citrullinated peptide antibodies.

PubMed

Vignesh, Ammapati Paul Pandian; Srinivasan, Renuka

2015-01-01

To study the ocular manifestations of rheumatoid arthritis and to correlate the role of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) with the ocular manifestations. Three-hundred and ninety-two eyes of the 196 rheumatoid arthritis patients who attended the ophthalmology outpatient department underwent a detailed ocular examination using slit lamp biomicroscopy and ophthalmoscopy. The tear function of all the patients was assessed using Schirmer's test, tear film break-up time and ocular surface staining. The anti-CCP antibody titers for all the rheumatoid arthritis patients were estimated using enzyme-linked immunosorbent assay tests. Seventy-seven patients (135 eyes, 39%) out of the 196 patients studied had ocular manifestations typical of rheumatoid arthritis. Dry eye was the most common manifestation (28%, 54 patients). Of the patients, 78% was females (60 patients). The mean duration of rheumatoid arthritis in patients with ocular manifestations was 5.4±2.7 years and without ocular manifestations was 2.1±1.6years. Three percent of the patients had episcleritis (six patients). Scleritis was present in 2% of the patients (four patients). Peripheral ulcerative keratitis and sclerosing keratitis was present in 1% of the population each (two patients each). Eighty-five percent (66 patients) had bilateral manifestations 15% (eleven patients) had unilateral manifestations. There was a strong association between the presence of anti-CCP antibodies and ocular manifestations of rheumatoid arthritis which was shown by the statistically significant P-value of <0.0001. Ocular manifestations are a significant part of the extra-articular manifestation of rheumatoid arthritis. Dry eye was the most common ocular manifestation. There was a statistically significant association between the presence of anti-CCP antibodies specific to rheumatoid arthritis and the ocular manifestations.

Restoration of Corneal Transparency by Mesenchymal Stem Cells.

PubMed

Mittal, Sharad K; Omoto, Masahiro; Amouzegar, Afsaneh; Sahu, Anuradha; Rezazadeh, Alexandra; Katikireddy, Kishore R; Shah, Dhvanit I; Sahu, Srikant K; Chauhan, Sunil K

2016-10-11

Transparency of the cornea is indispensable for optimal vision. Ocular trauma is a leading cause of corneal opacity, leading to 25 million cases of blindness annually. Recently, mesenchymal stem cells (MSCs) have gained prominence due to their inflammation-suppressing and tissue repair functions. Here, we investigate the potential of MSCs to restore corneal transparency following ocular injury. Using an in vivo mouse model of ocular injury, we report that MSCs have the capacity to restore corneal transparency by secreting high levels of hepatocyte growth factor (HGF). Interestingly, our data also show that HGF alone can restore corneal transparency, an observation that has translational implications for the development of HGF-based therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Ophthalmic applications of confocal microscopy: diagnostics, refractive surgery, and eye banking

NASA Astrophysics Data System (ADS)

Masters, Barry R.

1990-11-01

Confocal microscopy of ocular tissue provides two advantages over traditional imaging techniques: increased range and transverse resolution and increased contrast. The semitransparent cornea and ocular lens in the living eye can be optically sectioned and observed by reflected light confocal microscopy. Within the cornea we observed various cell components nerve fibers nerve cell bodies and fibrous networks. The confocal microscopic images from the in-situ ocular lens show the lens capsule the lens epithelium and the individual lens fibrils. All of the reflected light confocal microscopic images have high contrast and high resolution. Some of the applications of confocal imaging in ophthalmology include: diagnostics of the cornea and the ocular lens examination prior to and after refractive surgery examination of intraocular lenses (IOL) and examination of eye bank material. Other ophthalmic uses of confocal imaging include: studies of wound healing therapeutics and the effects of contact lenses on the cornea. The proposed features of a clinical confocal microscope are reviewed. 2.

[Depiction of the structure of the vitreous body in horses without ocular diseases and in horses with equine recurrent uveitis (ERU) using transmission electron microscopy].

PubMed

Niedermaier, G; Wollanke, B; Hoffmann, R; Matiasek, K; Gerhards, H

2006-06-01

Neither the ultrastructure of the vitreous body from horses without ocular diseases, nor the pathomorphological changes in the vitreous body associated with equine recurrent uveitis (ERU) have been described. However, the vitreous body plays an important role in the pathogenesis of ERU. Ten vitreous body samples obtained from 5 horses without ocular disease, and 38 vitreous body samples from horses with ERU (collected during vitrectomy) were examined by transmission electron microscopy. The vitreous body samples of horses without ocular diseases were characterized by a loose network of unbranched fibrils 10-12 nm in width. In the vitreous body samples of horses with ERU numerous dense bundles of fibrils, mononuclear inflammatory cells and necrotic cells represent the destruction of the vitreous fibrillar network. In this study, equine vitreous body ultrastructure was described for the first time. Thus, demonstrating ultramorphologically, the clinically apparent changes of the vitreous body associated with ERU.

Porcine retinal cell line VIDO R1 and Chlamydia suis to modelize ocular chlamydiosis.

PubMed

Käser, Tobias; Cnudde, Thomas; Hamonic, Glenn; Rieder, Meghanne; Pasternak, J Alex; Lai, Ken; Tikoo, Suresh K; Wilson, Heather L; Meurens, François

2015-08-15

Human ocular Chlamydia trachomatis infections can lead to trachoma, the major cause of infectious blindness worldwide. Trachoma control strategies are very helpful but logistically challenging, and a trachoma vaccine is needed but not available. Pigs are a valuable large animal model for various immunological questions and could facilitate the study of human ocular chlamydial infections. In addition, a recent study identified the zoonotic potential of Chlamydia suis, the natural pathogen of pigs. In terms of the One Health Initiative, understanding the host-pathogen-interactions and finding a vaccine for porcine chlamydia infections would also benefit human health. Thus, we infected the porcine retinal cell line VIDO R1 with C. suis and analyzed the chlamydial life cycle and the innate immune response of the infected cells. Our results indicate that C. suis completes its life cycle in VIDO R1 cells within 48 h, comparable to C. trachomatis in humans. C. suis infection of VIDO R1 cells led to increased levels of various innate immune mediators like pathogen recognition receptors, cytokines and chemokines including IL6, TNFα, and MMP9, also most relevant in human C. trachomatis infections. These results illustrate the first steps in the host-pathogen-interactions of ocular C. suis infections in pigs and show their similarity to C. trachomatis infections in humans, justifying further testing of pigs as an animal model for human trachoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Testing ocular irritancy in vitro with the silicon microphysiometer.

PubMed

Bruner, L H; Miller, K R; Owicki, J C; Parce, J W; Muir, V C

1991-01-01

The silicon microphysiometer, an instrument based on the light-addressable potentiometric sensor, was evaluated as an in vitro alternative for assessing ocular irritancy potential. It indirectly and non-invasively measures cell metabolism by determining the rate of acid metabolite production from cells, in this case human epidermal keratinocytes, placed inside the microphysiometer chamber. The 17 materials used for the evaluation included bar soaps, a liquid hand soap, shampoos, dishwashing liquids, laundry detergents, a fabric softener and several single chemicals. All materials tested were in liquid form. The in vivo irritancy potential of the materials was obtained from historical data using the rabbit low-volume eye test. There was a positive correlation between the in vivo irritancy potential of the test materials and the concentration of test material that decreased the acidification rate of cells by 50% (MRD(50); r = 0.86, P < 0.0001). Preliminary studies suggest other endpoints obtainable from the system may also provide useful information for making ocular safety assessments. Because the method is non-invasive, it is possible to determine whether cells recover from a treatment with the test material. The metabolic rate of the cells also increases at sub-inhibitory concentrations of some of the test materials. Because of the good correlation between the in vivo and in vitro data, the ease with which test materials can be applied to the system, and the multiple endpoints available from the system, it holds great potential as a useful in vitro alternative for ocular safety testing.

Stability of serum eye drops after storage of 6 months.

PubMed

Fischer, Kai R; Opitz, Andreas; Böeck, Markus; Geerling, Gerd

2012-11-01

Serum eye drops are used for the treatment of ocular surface disease (eg, Sicca syndrome). The objective of this experimental study was to investigate whether they maintain their wound-healing potency after a prolonged storage of 6 months at -20 °C and to find a parameter that can serve as a quality and stability indicator. After obtaining whole blood from 10 volunteers and preparing 100% (AS100), 50% (AS50), and 20% (AS20) serum eye drops, epitheliotrophic factors including EGF, fibronectin, vitamins A and E, albumin, and immunoglobulin A were quantified before and after storage for 7 days at 6 °C or 3 and 6 months at -20 °C. Human corneal epithelial (HCE) cell lines were used to investigate proliferation, migration, and overall wound healing potency of the cells in response to different serum preparations. The proliferation, migration, and wound healing of HCE cells were measured after incubation with different serum eye drop concentrations and after different storage conditions. The concentration of epidermal growth factor, fibronectin, vitamins A and E, immunoglobulin A, and albumin showed no significant reduction over the test period. Proliferation, migration, and wound healing of HCE cells was significantly better after incubation with undiluted serum in comparison with diluted serum. No significant loss of cytokine concentration, wound healing, and proliferation effect in HCE culture of AS100, AS50, and AS20 could be detected over the 6 months of storage. The concentration of a spectrum of cytokines involved in corneal epithelial wound healing and the epitheliothrophic effect of serum are not significantly changed after a prolonged storage of 6 months at -20 °C. Hence, it seems justifiable to provide patients with appropriate freezer capacity with a 6-month supply of autologous serum eye drops. Albumin--which is known to be relevant for ocular surface health--could serve as a cost-effective parameter for stability controls.

Transport and interaction of cosmetic product material within the ocular surface: beauty and the beastly symptoms of toxic tears.

PubMed

Malik, Adeela; Claoué, Charles

2012-12-01

Eye cosmetics such as mascara, eye shadow and eyeliner are used extensively to highlight the eyes, and are normally applied external to the ocular surface. Adverse reactions of cosmetics within the ocular surface include mild discomfort, eyelid dermatitis, pre-corneal tear film instability, and keratitis. These are attributed mainly to the preservative (benzalkonium chloride (BAC)) constituent of cosmetic product material (CPM). Transport of CPM from an external environment to any location on the ocular surface, essentially precedes the adverse interactions occurring at the location, and the control of these transport modes is therefore of clinical relevance. The inter-transport of CPM across the TF occurs due to both diffusion and drift processes. Diffusion of neutral species is driven by concentration gradients, and the drift of cationic BAC is influenced by the inherent electric field; determined by the distribution of the various ions secreted into the aqueous layer, and the negative glycocalyx charge at the mucin layer. In the presence of mucin deficiency, the corneal epithelium is exposed to invasion by both incident BAC and lipophilic species. The transport of cationic BAC across the TF may be controlled by regulating the secretion of various electrolytes at the lacrimal gland. This is of clinical significance in reducing corneal epithelial adverse effects. However, the risks of adverse effects at the corneal surface due to invasion by the lipophilic species remain. Patients with mucin deficiency, and especially those on eye ointment/drops medication, should be discouraged from using cosmetics in a way likely to contaminate the TF. Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Case control study of dry eye and related ocular surface abnormalities in Ibadan, Nigeria.

PubMed

Bekibele, C O; Baiyeroju, A M; Ajaiyeoba, A; Akang, E E U; Ajayi, B G K

2010-02-01

Tear instability is associated with symptoms of ocular discomfort and irritation. Many patients with dry eyes remain untreated due to improper diagnoses. To identify symptoms and surface abnormalities associated with dry eyes. One hundred and fifty-six eyes of 78 subjects attending the Eye Clinic of the University College Hospital Ibadan were screened for dry eyes/tear instability using rose Bengal stain (graded 0-9), tear break-up time (TBUT), Schirmer's 1 tests, tear meniscus height and a standardised symptoms questionnaire. Grades 4-9 rose Bengal staining were considered as positive dry eye and were compared with grades 0-3 staining eyes as negative controls. Mean tear meniscus height, Schirmer's test and TBUT were lower among cases than their corresponding control eyes. The difference between the mean Schirmer's test values of cases and their controls were statistically significant (P = 0.00 for right eyes and P = 0.002 for left eyes). Rose Bengal grades were inversely correlated with the mean Schirmer's values (Pearson correlation -0.429, P = 0.05 for right eyes and -0.335, P = 0.03 for left eyes) and TBUT (Pearson correlation -0.316, P = 0.05 for right eyes and -0.212, P = 0.06 for left eyes). About 95.8% of the cases were symptomatic, as opposed to 70.4% of the controls (P = 0.01, Fisher's exact test) and 95.8% of dry right eyes compared to 61.1% of their controls had ocular surface abnormalities (P = 0.001), while 89.5% of dry left eyes compared to 62.7% of controls had surface abnormalities (P = 0.07). A close relationship exists between ocular irritation symptoms, surface abnormalities and functional evidence of tear instability. Such patients should be treated empirically or screened for dry eyes.

The Effects of Increasing Ocular Surface Stimulation on Blinking and Sensation

PubMed Central

Wu, Ziwei; Begley, Carolyn G.; Situ, Ping; Simpson, Trefford

2014-01-01

Purpose. The purpose of this study was to determine how increasing ocular surface stimulation affected blinking and sensation, while controlling task concentration. Methods. Ten healthy subjects concentrated on a task while a custom pneumatic device generated air flow toward the central cornea. Six flow rates (FRs) were randomly presented three times each and subjects used visual analog scales to record their sensory responses. The interblink interval (IBI) and the FR were recorded simultaneously and the IBI, sensory response, and corresponding FR were determined for each trial. The FR associated with a statistically significant decrease in IBI, the blink increase threshold (BIT), was calculated for each subject. Results. Both the mean and SD of IBI were decreased with increasing stimulation, from 5.69 ± 3.96 seconds at baseline to 1.02 ± 0.37 seconds at maximum stimulation. The average BIT was 129 ± 20 mL/min flow rate with an IBI of 2.33 ± 1.10 seconds (permutation test, P < 0.001). After log transformation, there was a significant linear function between increasing FR and decreasing IBI within each subject (Pearson's r ≤ −0.859, P < 0.05). The IBI was highly correlated with wateriness, discomfort, and cooling ratings (Pearson's r ≤ −0.606, P < 0.001). Conclusions. There was a dose-response–like relationship between increased surface stimulation and blinking in healthy subjects, presumably for protection of the ocular surface. The blink response was highly correlated with ocular surface sensation, which is not surprising given their common origins. The BIT, a novel metric, may provide an additional end point for studies on dry eye or other conditions. PMID:24557346

Long-term topical application of preservative-free prostaglandin analogues evokes macrophage infiltration in the ocular adnexa.

PubMed

Trzeciecka, Anna; Paterno, J Jussi; Toropainen, Elisa; Koskela, Ali; Podracka, Lucia; Korhonen, Eveliina; Kauppinen, Anu; Kaarniranta, Kai; Smedowski, Adrian

2016-10-05

Success of the long-term glaucoma therapy and preservation of the visual function strongly depend on patients' compliance which may be affected by the inconvenience of treatment and its side effects. Recently, introduction of preservative-free anti-glaucoma agents has become an important step towards improved glaucoma care by eliminating the negative effects of preservatives on the eye surface. Although, newly developed eye drop formulations do not contain standard preservatives, they still can be harmful to ocular surface due to other excipients. In this study, we compared tolerability of commercial preservative-free (pf) prostaglandin analogues (pf tafluprost, pf latanoprost and pf bimatoprost) in long-term topical application in rabbits in vivo. We found that after eight weeks treatment, pf latanoprost was the worst tolerated among the tested drops. It expressed increased conjunctival redness and blinking frequency. Furthermore, it caused increased LDH release in the aqueous humour, infiltration of macrophages in the eyelids and visible defects in conjunctival goblet cells. However, we did not detect increased levels of inflammatory markers in the tear fluid or in the aqueous humour. Based on our study, we suspect that these negative effects are related to excipients included in pf latanoprost formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of poly(2-hydroxyethyl methacrylate) and poly(vinyl-pyrrolidone) hydrogel implants on myopic and normal chick sclera

PubMed Central

Su, James; Iomdina, Elena; Tarutta, Elena; Ward, Brian; Song, Jie; Wildsoet, Christine F.

2008-01-01

There has been generally little attention paid to the utilization of biomaterials as an anti-myopia treatment. The purpose of this study was to investigate whether polymeric hydrogels, either implanted or injected adjacent to the outer scleral surface, slow ocular elongation. White Leghorn (gallus gallus domesticus) chicks were used at 2 weeks of age. Chicks had either (1) strip of poly(2-hydroxyethyl methacrylate) (pHEMA) implanted monocularly against the outer sclera at the posterior pole, or (2) an in situ polymerizing gel [main ingredient: poly(vinyl-pyrrolidone) (PVP)] injected monocularly at the same location. Some of the eyes injected with the polymer were fitted with a diffuser or a −10D lens. In each experiment, ocular lengths were measured at regular intervals by high frequency A-scan ultrasonography, and chicks were sacrificed for histology at staged intervals. No in vivo signs of either orbital or ocular inflammation were observed. The pHEMA implant significantly increased scleral thickness by the third week, and the implant became encapsulated with fibrous tissue. The PVP-injected eyes left otherwise untreated, showed a significant increase in scleral thickness, due to increased chondrocyte proliferation and extracellular matrix deposition. However, there was no effect of the PVP injection on ocular elongation. In eyes wearing optical devices, there was no effect on either scleral thickness or ocular elongation. These results represent “proof of principle” that scleral growth can be manipulated without adverse inflammatory responses. However, since neither approach slowed ocular elongation, additional factors must influence scleral surface area expansion in the avian eye. PMID:19109950

A Novel Combination Therapy for Patients With Dry Eye Disease: A Pilot Study.

PubMed

Smith, Will; McMahon, David; Nymark, Maria

2018-05-01

Context • Approximately 25% of the US population suffers from dry eyes or some abnormality of the exposed ocular surface. Investigation of effective modalities for their management is needed. Objective • The study intended to examine the efficacy of a proprietary, daily, Dry Eye Protocol consisting of daily use of a moist, heated, ocular compress and intake of an omega-3 dietary supplement in treatment of ocular surface disease. Design • The research team designed a 4-wk, clinically based, open-label, multicenter cohort study. Setting • The study took place at 6 private eye care practices throughout the United States: Beverly Hills, CA, USA; San Diego, CA, USA; Sunnyvale, CA, USA; Park City, UT, USA; Tarpon Spring, FL, USA; and Kennewick, WA, USA. Participants • Participants were adults between 18 and 75 y of age who had established ocular surface disease based on clinical findings and the results of testing using the ocular surface disease index (OSDI). Intervention • For period of 30 d, participants used a combined daily protocol that included (1) application of a moist, heated, eye compress and (2) a nutritional therapy via an omega-3 supplement in an oral triglyceride form. Outcome Measures • Measures included the OSDI and a test of tear break-up time (TBUT). Results • Of the original 35 participants, 33 completed the 4-wk protocol. The participants using the proprietary Dry Eye Protocol showed significant improvements from baseline, demonstrated by a 49% decrease in OSDI scores (P = .0015); and 46% of participants reported becoming asymptomatic of dry eye symptoms. A significant improvement was also observed in TBUT, increasing from 3.0 to 5.4 s. Conclusions • Daily use of the proprietary Dry Eye Protocol that included a high dosage of triglyceride omega-3 and use of a moist, heated, compress daily showed significant improvement for participants in OSDI and TBUT and should be considered to be a first-line therapy for patients with dry eye disease.

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

PubMed Central

Jwala, Jwala; Boddu, Sai H.S.; Shah, Sujay; Sirimulla, Suman; Pal, Dhananjay

2011-01-01

Abstract Purpose The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-L-valine-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Methods Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. Results L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of L-valine-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Conclusion Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration. PMID:21500985

Structural and functional maturation of skin during metamorphosis in the Atlantic halibut (Hippoglossus hippoglossus).

PubMed

Alves, Ricardo N; Sundell, Kristina S; Anjos, Liliana; Sundh, Henrik; Harboe, Torstein; Norberg, Birgitta; Power, Deborah M

2018-06-01

To establish if the developmental changes in the primary barrier and osmoregulatory capacity of Atlantic halibut skin are modified during metamorphosis, histological, histochemical, gene expression and electrophysiological measurements were made. The morphology of the ocular and abocular skin started to diverge during the metamorphic climax and ocular skin appeared thicker and more stratified. Neutral mucins were the main glycoproteins produced by the goblet cells in skin during metamorphosis. Moreover, the number of goblet cells producing neutral mucins increased during metamorphosis and asymmetry in their abundance was observed between ocular and abocular skin. The increase in goblet cell number and their asymmetric abundance in skin was concomitant with the period that thyroid hormones (THs) increase and suggests that they may be under the control of these hormones. Several mucin transcripts were identified in metamorphosing halibut transcriptomes and Muc18 and Muc5AC were characteristic of the body skin. Na + , K + -ATPase positive (NKA) cells were observed in skin of all metamorphic stages but their number significantly decreased with the onset of metamorphosis. No asymmetry was observed between ocular and abocular skin in NKA cells. The morphological changes observed were linked to modified skin barrier function as revealed by modifications in its electrophysiological properties. However, the maturation of the skin functional characteristics preceded structural maturation and occurred at stage 8 prior to the metamorphic climax. Treatment of Atlantic halibut with the THs disrupter methimazole (MMI) affected the number of goblet cells producing neutral mucins and the NKA cells. The present study reveals that the asymmetric development of the skin in Atlantic halibut is TH sensitive and is associated with metamorphosis and that this barrier's functional properties mature earlier and are independent of metamorphosis.

Genome-Wide Identification of Circular RNAs as a Novel Class of Putative Biomarkers for an Ocular Surface Disease.

PubMed

Li, Xiu-Miao; Ge, Hui-Min; Yao, Jin; Zhou, Yun-Fan; Yao, Mu-Di; Liu, Chang; Hu, Hai-Tao; Zhu, Yun-Xi; Shan, Kun; Yan, Biao; Jiang, Qin

2018-06-27

Pterygium is a common ocular surface disease with an unknown etiology and threatens vision as it invades into the cornea. Circular RNAs (circRNAs) are a novel class of RNA transcripts that participate in several physiological and pathological processes. However, the role of circRNAs in pathogenesis of pterygium remains largely unknown. Genome-wide circRNA expression profiling was performed to identify pterygium -related circRNAs. GO analysis, pathway analysis, and miRNA response elements analysis was performed to predict the function of differentially expressed circRNAs in pterygium. MTT assays, Ki67 staining, Transwell assay, Hoechst 33342 staining, and Calcein-AM/PI staining were performed to determine the effect of circRNA silencing on pterygium fibroblast and epithelial cell function. Approximately 669 circRNAs were identified to be abnormally expressed in pterygium tissues. GO analysis demonstrated that the host genes of differentially expressed circRNAs were targeted to extracellular matrix organization (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis showed that dysregulated circRNAs-mediated regulatory networks were mostly enriched in focal adhesion signaling pathway. Notably, circ_0085020 (circ-LAPTM4B) was shown as a potential biomarker for pterygium. circ_0085020 (circ-LAPTM4B) silencing affected the viability, proliferation, migration, and apoptosis of pterygium fibroblast and epithelial cells in vitro. This study provides evidence that circRNAs are involved in the pathogenesis of pterygium and might constitute promising targets for the therapeutic intervention of pterygium. © 2018 The Author(s). Published by S. Karger AG, Basel.

[Ocular graft-versus-host disease: An often misdiagnosed etiology of dry eye syndrome].

PubMed

Moyal, L; Adam, R; Akesbi, J; Rodallec, F T; Nordmann, J-P

2017-02-01

To report a case of severe ocular graft-versus-host disease (GVHD) after cataract surgery. Observational case report. We describe the case of a 59-year-old man with postoperative corneal ulcer on his only functional eye. His past history reported allogenic bone marrow transplant. His visual acuity (VA) was limited to hand motions. Slit lamp examination revealed diffuse conjunctival hyperemia, severe blepharitis, Meibomian dysfunction, total corneal opacification with epithelial and stromal keratitis and neovascular invasion. Because of the severe dry eye symptoms and history of allogenic hematological stem cell transplantation, ocular GVHD was diagnosed. Functional and anatomical improvement occurred rapidly with topical cyclosporine 2%, with improved VA after treatment. With any severe dry eye syndrome in the context of allogenic bone marrow transplant, ocular GVHD must be considered. For planned ocular surgery, we recommend adding cyclosporine 0.1% treatment before and after surgery to prevent severe ocular GVHD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Hypercholesterolemia-induced ocular disorder: Ameliorating role of phytotherapy.

PubMed

El-Sayyad, Hassan I H; Elmansi, Ahmed A; Bakr, Eman H M

2015-01-01

The ocular region is a complex structure that allows conscious light perception and vision. It is of ecto-mesodermal origin. Cholesterol and polyunsaturated fatty acids are involved in retinal cell function; however, hypercholesterolemia and diabetes impair its function. Retinal damage, neovascularization, and cataracts are the main complications of cholesterol overload. Dietary supplementation of selected plant products can lead to the scavenging of free reactive oxygen species, thereby protecting the ocular regions from the damage of hypercholesterolemia. This review illustrates the dramatic effects of increased cholesterol levels on the ocular regions. The effect of phytotherapy is discussed in relation to the different regions of the eye, including the retina, cornea, and lens. Copyright © 2015 Elsevier Inc. All rights reserved.

Design and elaboration of freeze-dried PLGA nanoparticles for the transcorneal permeation of carprofen: Ocular anti-inflammatory applications.

PubMed

Parra, Alexander; Mallandrich, Mireia; Clares, Beatriz; Egea, María A; Espina, Marta; García, María L; Calpena, Ana C

2015-12-01

This work aimed the design and development of poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) for the ocular delivery of Carprofen (CP) by a central rotatable composite design 2(3)+ star. NPs showed adequate size for ocular administration (189.50 ± 1.67 nm), low polydispersity (0.01 ± 0.01), negative charge surface (-22.80 ± 0.66 mV) and optimal entrapment efficiency (74.70 ± 0.95%). Physicochemical analysis confirmed that CP was dispersed inside the NPs. The drug release followed a first order kinetic model providing greater sustained CP release after lyophilization. Ex vivo permeation analysis through isolated rabbit cornea revealed that a sufficient amount of CP was retained in the tissue avoiding excessive permeation and thus, potential systemic levels. Ex vivo ocular tolerance results showed no signs of ocular irritancy, which was also confirmed by in vivo Draize test. In vivo ocular anti-inflammatory efficacy test confirmed an optimal efficacy of NPs and its potential application in eye surgery. Copyright © 2015 Elsevier B.V. All rights reserved.

Ocular findings in acquired immunodeficiency syndrome patients in Lagos, Nigeria.

PubMed

Onakoya, A O; Odeyemi, M G; Aribaba, O T; Akinsola, F B

2012-01-01

There is paucity of studies on the prevalence and pattern of ocular complication in HIV patients in developing countries where 90% of all HIV sufferers live. Most studies were carried out in industrialized countries and are not representative of the spectrum of ocular complication of HIV and it's prevalence in developing countries. To determine the prevalence of ocular disorders in adult (> 15 years ) AIDS patients at PEPFAR clinic in Lagos, Nigeria. All consecutive adult Seropositive HIV/AIDS patients of PEPFAR Clinic at the Lagos University Teaching Hospital between February 1st-March 15th 2008 were enrolled into the study Cross sectional and non randomized, convenient study was used. Biodata and medical history were recorded on interviewer administered questionnaire. Participants were examined according to standard protocol comprising visual acuity, intraocular pressure, anterior segment examination with slit lamp biomicroscopy, dilated fundoscopy and fundus photograph where necessary. PCV, CD4+ count, viral load at diagnosis, stage of HIV disease were extracted from patients' records. Details of drug were regimen also recorded. Data analysis was performed with EPI-lnfo 6.04 version; Chi square and student t test used to describe statistical association. A total of 400 patients were studied. Male:female ratio was 1.7 and mean age was 40 years (S.D. + 9.12). Ocular disorders seen in 78.5% of patients; HIV related ocular disorders occurred in 45 (11.3) patients. Conjunctival microvasculopathy 166 patients (41.5%), pingueculum in 114 (28.5%), pterygium in 76 (19.0%), refractive error in 93 (23.3%), cataract in 12 (3.0%), and 22 (5.5%) Glaucoma suspects. HIV retinopathy and allergic eye disease in one patient each (0.3%). Presumed Cytomegalovirus retinitis 7 (1.8%), 14 (3.5%) Toxoplasmosis, 8 (2.0%) HZO, and 15 (3.8%) Presumed Squamous cell carcinoma. Eighty six (21.5%) of the patients had no abnormality. 91.4% of eyes examined had visual acuity with best correction of > 6/18. CD4+ in 79.3% of the patients was > 200 cells/ul and < 5% had counts < 50 cells with an overall mean of 406 cell/ul. 375 (93.8%) patients were on Highly Active Antiretroviral therapy (HAART), and 25 (6.2%) were not. Study revealed low prevalence of HIV related ocular disorders. This could be due to few patients at low level of immunosuppresion where the infections occur.

Incomplete response to artificial tears is associated with features of neuropathic ocular pain.

PubMed

Galor, Anat; Batawi, Hatim; Felix, Elizabeth R; Margolis, Todd P; Sarantopoulos, Konstantinos D; Martin, Eden R; Levitt, Roy C

2016-06-01

Artificial tears are first-line therapy for patients with dry eye symptoms. It is not known, however, which patient factors associate with a positive response to therapy. The purpose of this study was to evaluate whether certain ocular and systemic findings are associated with a differential subjective response to artificial tears. Cross-sectional study of 118 individuals reporting artificial tears use (hypromellose 0.4%) to treat dry eye-associated ocular pain. An evaluation was performed to assess dry eye symptoms (via the dry eye questionnaire 5 and ocular surface disease index), ocular and systemic (non-ocular) pain complaints and ocular signs (tear osmolarity, tear breakup time, corneal staining, Schirmer testing with anaesthesia, and eyelid and meibomian gland assessment). The main outcome measures were factors associated with differential subjective response to artificial tears. By self-report, 23 patients reported no improvement, 73 partial improvement and 22 complete improvement in ocular pain with artificial tears. Patients who reported no or partial improvement in pain with artificial tears reported higher levels of hot-burning ocular pain and sensitivity to wind compared with those with complete improvement. Patients were also asked to rate the intensity of systemic pain elsewhere in the body (other than the eye). Patients who reported no or incomplete improvement with artificial tears had higher systemic pain scores compared with those with complete improvement. Both ocular and systemic (non-ocular) pain complaints are associated with a differential subjective response to artificial tears. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease.

PubMed

Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

2015-08-01

To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). Prospective study. Eighty-four patients diagnosed with chronic ocular GVHD. We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Vision-Related Quality of Life in Patients with Ocular Graft-versus-host Disease

PubMed Central

Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

2015-01-01

Objective To assess the vision-related quality of life in a cohort of patients with ocular graft-versus-host disease (GVHD). Design Prospective study. Participants Eighty-four patients diagnosed with chronic ocular GVHD Methods We assessed the vision-related quality of life with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. Main outcome measures We assessed vision-related quality of life with NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD to those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and dry eye symptoms measured by OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity, corneal fluorescein staining, tear break-up time, and Schirmer test. Results The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5 ± 17. Compared to healthy subjects, ocular GVHD patients reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = −0.81, P < 0.001), SANDE (R = −0.56, P < 0.001), corneal fluorescein staining (R = −0.36, P = 0.001) and best-corrected visual acuity (R = −0.30, P = 0.004). Conclusion Patients with ocular GVHD experience measurable impairment of vision-related quality of life. This study highlights the impact of ocular GVHD on the vision-related quality of life, and hence the importance of comprehensive diagnosis and treatment of this condition. PMID:26001816

We are not alone: a case for the human microbiome in extra intestinal diseases.

PubMed

Shivaji, S

2017-01-01

"Dysbiosis" in the gut microbiome has been implicated in auto-immune diseases, in inflammatory diseases, in some cancers and mental disorders. The challenge is to unravel the cellular and molecular basis of dysbiosis so as to understand the disease manifestation. Next generation sequencing and genome enabled technologies have led to the establishment of the composition of gut microbiomes and established that "dysbiosis" is the cause of several diseases. In a few cases the cellular and molecular changes accompanying dysbiosis have been investigated and correlated with the disease. Gut microbiome studies have indicated that Christensenella minuta controls obesity in mice, Faecalibacterium prausnitzii protects mice against intestinal inflammation and Akkermansia muciniphila reverses obesity and insulin resistance by secreting endocannabinoids. In mice polysaccharide antigen A on the surface of Bacteroides fragilis , reduces inflammation. Such experiments provide the link between the gut microbiome and human health but implicating dysbiosis with extra-intestinal diseases like arthritis, muscular dystrophy, vaginosis, fibromyalgia, some cancers and mental disorders appears to be more challenging. The relevance of gut microbiome to the eye appears to be very remote. But considering that the eye is the site of inflammatory diseases like uveitis, scleritis, Mooren's corneal ulcer etc. it is possible that these diseases are also influenced by dysbiosis. In mice signals from the gut microbiota activate retina specific T cells that are involved in autoimmune uveitis. Such information would open up new strategies for therapy where the emphasis would be on restoring the diversity in the gut by antibiotic or specific drug use, specific microbe introduction, probiotic use and fecal transplant therapy. The ocular surface microbiome may also be responsible for eye diseases in man but such studies are lacking. Microbiome of the healthy cornea and conjunctiva have been identified. But whether the ocular microbiome exhibits dysbiosis with disease? Whether ocular microbiome is influenced by the gut microbiome? What mediates the cross-talk between the gut and ocular microbiomes? These are questions that need to be addressed to understand idiopathic infections of the eye. Evaluating diseases remote from the gut would unfold the mysteries of the microbiome.

Corneal Sensitivity in Tear Dysfunction and its Correlation with Clinical Parameters and Blink Rate

PubMed Central

Rahman, Effie Z.; Lam, Peter K.; Chu, Chia-Kai; Moore, Quianta; Pflugfelder, Stephen C.

2015-01-01

Purpose To compare corneal sensitivity in tear dysfunction due to a variety of causes using contact and non-contact esthesiometers and to evaluate correlations between corneal sensitivity, blink rate and clinical parameters. Design Comparative observational case series. Methods Ten normal and 33 subjects with tear dysfunction [meibomian gland disease (n = 11), aqueous tear deficiency (n = 10) - without (n = 7) and with (n = 3) Sjögren syndrome (SS) and conjunctivochalasis (n = 12)] were evaluated. Corneal sensitivity was measured with Cochet-Bonnet and air jet esthesiometers and blink rate by electromyelography. Eye irritation symptoms, tear meniscus height, tear break-up time (TBUT), and corneal and conjunctival dye staining were measured. Between group means were compared and correlations calculated. Results Compared with control (Cochet-Bonnet 5.45 mm, air esthesiometer 3.62 mg), mean sensory thresholds were significantly higher in aqueous tear deficiency using either Cochet-Bonnet (3.6 mm; P = 0.003) or air (11.7 mg; P = 0.046) esthesiometers, but were not significantly different in the other groups. Reduced corneal sensitivity significantly correlated with more rapid TBUT and blink rate, and greater irritation and ocular surface dye staining with one or both esthesiometers. Mean blink rates were significantly higher in both aqueous tear deficiency and conjunctivochalasis compared with control. Among all subjects, blink rate positively correlated with ocular surface staining and irritation and inversely correlated with TBUT. Conclusion Amongst conditions causing tear dysfunction, reduced corneal sensitivity is associated with greater irritation, tear instability, ocular surface disease and blink rate. Rapid blinking is associated with worse ocular surface disease and tear stability. PMID:26255576

Efficacy of punctal occlusion in management of dry eyes after laser in situ keratomileusis for myopia.

PubMed

Alfawaz, Abdullah M; Algehedan, Saeed; Jastaneiah, Sabah S; Al-Mansouri, Samir; Mousa, Ahmed; Al-Assiri, Abdullah

2014-03-01

To evaluate the effect of punctal plug use in preventing dry eye after laser in situ keratomileusis (LASIK). A randomized clinical trial at a tertiary eye care center, Riyadh, Saudi Arabia. Participants underwent LASIK for myopia in both eyes and a lower punctal occlusion in one eye only while the other eye served as control. Both eyes received the same postoperative medications except for lubricant duration (subject eye: four times per day for one week; control eye: four times per day for 6 months). Participants were evaluated at 1 week, 2, and 6 months after surgery for signs and symptoms of dry eye. The main outcome measures were visual acuity; ocular surface parameters; and Ocular Surface Disease Index questionnaire. Seventy-eight eyes of 39 patients were included in this study. The Ocular Surface Disease Index scores of eyes with punctal plugs were better at all follow-up visits, and the differences between both eyes were statistically significant (1 week, p < 0.0001; 2 months, p < 0.0001; 6 months, p = 0.008). At the final follow-up visit, the percentage of normal eyes was higher in eyes with punctal plugs for all ocular surface parameters (Schirmer 1 test, 94.9%; tear breakup time, 77.8%; punctate epithelial keratitis score, 71.8%) compared to eyes without occlusion (Schirmer 1 test, 92.3%; tear breakup time, 58.3%; punctate epithelial keratitis score, 53.8%); however, such differences were not statistically significant. Punctal plug insertion after LASIK surgeries may minimize the need for frequent lubricant application and hence improve patient satisfaction.

Tear cytokine profile as a noninvasive biomarker of inflammation for ocular surface diseases: standard operating procedures.

PubMed

Wei, Yi; Gadaria-Rathod, Neha; Epstein, Seth; Asbell, Penny

2013-12-23

To provide standard operating procedures (SOPs) for measuring tear inflammatory cytokine concentrations and to validate the resulting profile as a minimally invasive objective metric and biomarker of ocular surface inflammation for use in multicenter clinical trials on dry eye disease (DED). Standard operating procedures were established and then validated with cytokine standards, quality controls, and masked tear samples collected from local and distant clinical sites. The concentrations of the inflammatory cytokines in tears were quantified using a high-sensitivity human cytokine multiplex kit. A panel of inflammatory cytokines was initially investigated, from which four key inflammatory cytokines (IL-1β, IL-6, INF-γ, and TNF-α) were chosen. Results with cytokine standards statistically satisfied the manufacturer's quality control criteria. Results with pooled tear samples were highly reproducible and reliable with tear volumes ranging from 4 to 10 μL. Incorporation of the SOPs into clinical trials was subsequently validated. Tear samples were collected at a distant clinical site, stored, and shipped to our Biomarker Laboratory, where a masked analysis of the four tear cytokines was successfully performed. Tear samples were also collected from a feasibility study on DED. Inflammatory cytokine concentrations were decreased in tears of subjects who received anti-inflammatory treatment. Standard operating procedures for human tear cytokine assessment suitable for multicenter clinical trials were established. Tear cytokine profiling using these SOPs may provide objective metrics useful for diagnosing, classifying, and analyzing treatment efficacy in inflammatory conditions of the ocular surface, which may further elucidate the mechanisms involved in the pathogenesis of ocular surface disease.

[Research progress of conscious pain and neurosensory abnormalities in dry eye disease].

PubMed

Lin, X; Liu, Z L; Wu, J L; Liu, Z G

2018-02-11

Dry eye is one of the most common ocular problems in ophthalmology clinic. With the change of social environment and people's life style, the prevalence of dry eye disease is increasing. Currently, the diagnosis criteria for dry eye is controversial, diagnosis of dry eye mainly rely on the comprehensive assessment of symptoms and the presence of associated ocular surface signs. However, previous studies have shown a poor correlation between dry eye symptoms and objective clinical signs in patients. Recent studies have found that neuropathic pain plays an important role in the occurrence of discordance between symptoms and signs in dry eye disease. The purpose of this paper is to present the conception of pain, the distribution and function of sensory nerves in ocular surface, the prevalence and mechanism of neuropathic pain and analgesic treatment in dry eye disease. (Chin J Ophthalmol, 2018, 54: 144-148) .

Correlation between acute conjunctivitis and Asian dust on ocular surfaces.

PubMed

Ko, Ryota; Hayashi, Masahiko; Hayashi, Hideyuki; Hayashi, Kazue; Kato, Hitoshi; Kurata, Yoshinori; Fuchino, Yuki; Nakamichi, Toshifumi; Migita, Hironori; Yano, Hiroko; Sakata, Tetsuya; Uchio, Eiichi

2016-01-01

The aim of this study was to determine the presence of Asian dust particles (ADP) in patients suffering from conjunctivitis and its correlation with clinical scores for conjunctivitis. Forty-five patients from the Fukuoka area who were newly diagnosed acute conjunctivitis were selected. The degrees of inflammatory reaction, itchy sensation, hyperemia, eye discharge, and foreign body sensation were clinically recorded and scored. Eyes were washed with physiological solution. Solid particles collected from the washing solution were observed using a scanning electron microscope. Of the 45 samples, 44 were positive for the elements silicon (Si) and aluminum (Al), which are components of ambient Asian dust. Higher conjunctivitis scores were found in the subgroup in which the Asian dust/whole particle ratio was greater than average. This is the first apparent report on the correlation between amount of ADP exposure at the ocular surface and severity of ocular symptoms.

Effects of lodoxamide (LOD), disodium cromoglycate (DSCG) and N-acetyl-aspartyl-glutamate sodium salt (NAAGA) on ocular active anaphylaxis.

PubMed

Goldschmidt, P; Luyckx, J

1996-04-01

LOD, DSCG and NAAGA eye-drops were evaluated on experimentally-induced ocular active anaphylaxis in guinea pigs. Twelve animals per group were sensitized with egg albumin i.p. and challenged on the surface of the eye 14 days later. Two days before challenge, animals were treated with LOD, DSCG or NAAGA 4 times a day. Permeability indexes were calculated after intracardiac injection of Evans Blue. No effect on ocular active anaphylaxis was found with LOD nor with DSCG. NAAGA was able to significantly reduce blood-eye permeability indexes.

Slit Lamp-Based Ocular Scoring Systems in Toxicology and Drug Development: A Literature Survey.

PubMed

Eaton, Joshua Seth; Miller, Paul E; Bentley, Ellison; Thomasy, Sara M; Murphy, Christopher J

2017-12-01

To present a survey of the features of published slit lamp-based scoring systems and their applicability in the context of modern ocular toxicology and drug development. References describing original or modified slit lamp-based scoring systems for human or veterinary clinical patients or in investigative or toxicologic research were collected following a comprehensive literature review using textbooks and online publication searches. Each system's indications and features were compiled to facilitate comparison. Literature review identified 138 original or modified scoring systems. Most (48%) were published for evaluation of the ocular surface, 34% for the general anterior segment, and 18% for the lens. Most systems were described for assessment of human patients (50%) and small albino laboratory species such as rabbits (19%), rats (12%), and mice (8%). Systems described for pigmented laboratory species and for larger species such as dogs, cats, pigs, and nonhuman primates (NHPs) were comparatively underrepresented. No systems described a lens scoring scheme specific to the dog, cat, pig, or NHP. Scoring schemes for aqueous and vitreous cells were infrequently described for laboratory species. Many slit lamp-based scoring systems have been published, but the features of each differ and complicate translation of findings between different species. Use and interpretation of any scoring system in toxicology and drug development must be done with awareness of the limitations of the system being used.

Ophthalmic Manifestations and Histopathology of Xeroderma Pigmentosum: Two Clinicopathological Cases and a Review of the Literature

PubMed Central

Ramkumar, Hema L.; Brooks, Brian P.; Cao, Xiaoguang; Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.; Chan, Chi-Chao

2011-01-01

Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the UV exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. We report the clinical history and ocular pathology of two Caucasian women who had xeroderma pigmentosum with neurological degeneration: Case 1, who died at age 44 and Case 2, who died at age 45. Case 1 with mutations in the XPA gene, had more than 180 basal cell carcinomas of her skin and eyelids and died from complications of neurodegeneration. Case 2, with mutations in the XPD gene, was sun protected and had 3 skin cancers. She died from complications of neurodegeneration and pneumonia. Both patients had bilateral pinguecula, corneal pannus and exposure keratopathy. Case 1 had bilateral optic atrophy, while Case 2 had bilateral peripheral retinal pigmentary degeneration. Both patients developed retinal gliosis. The ophthalmic manifestations and pathology of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina. PMID:21684361

Ophthalmic manifestations and histopathology of xeroderma pigmentosum: two clinicopathological cases and a review of the literature.

PubMed

Ramkumar, Hema L; Brooks, Brian P; Cao, Xiaoguang; Tamura, Deborah; Digiovanna, John J; Kraemer, Kenneth H; Chan, Chi-Chao

2011-01-01

Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. We report the clinical history and ocular pathology of two white women who had xeroderma pigmentosum with neurological degeneration: Case 1 (died at age 44 years) and Case 2 (died at age 45 years). Case 1, with mutations in the XPA gene, had more than 180 basal cell carcinomas of her skin and eyelids and died from complications of neurodegeneration. Case 2, with mutations in the XPD gene, was sun-protected and had three skin cancers. She died from complications of neurodegeneration and pneumonia. Both patients had bilateral pinguecula, corneal pannus, and exposure keratopathy. Case 1 had bilateral optic atrophy, and Case 2 had bilateral peripheral retinal pigmentary degeneration. Both patients developed retinal gliosis. The ophthalmic manifestations and pathology of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina. Published by Elsevier Inc.

Cyclodextrin Enhances Corneal Tolerability and Reduces Ocular Toxicity Caused by Diclofenac

PubMed Central

Abdelkader, Hamdy; Fathalla, Zeinab; Moharram, Hossam; Ali, Taha F. S.

2018-01-01

With advances in refractive surgery and demand for cataract removal and lens replacement, the ocular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased. One of the most commonly used NSAIDs is diclofenac (Diclo). In this study, cyclodextrins (CDs), α-, β-, γ-, and HP-β-CDs, were investigated with in vitro irritation and in vivo ulceration models in rabbits to reduce Diclo toxicity. Diclo-, α-, β-, γ-, and HP-β-CD inclusion complexes were prepared and characterized and Diclo-CD complexes were evaluated for corneal permeation, red blood cell (RBCs) haemolysis, corneal opacity/permeability, and toxicity. Guest- (Diclo-) host (CD) solid inclusion complexes were formed only with β-, γ-, and HP-β-CDs. Amphipathic properties for Diclo were recorded and this surfactant-like functionality might contribute to the unwanted effects of Diclo on the surface of the eye. Contact angle and spreading coefficients were used to assess Diclo-CDs in solution. Reduction of ocular toxicity 3-fold to16-fold and comparable corneal permeability to free Diclo were recorded only with Diclo-γ-CD and Diclo-HP-β-CD complexes. These two complexes showed faster healing rates without scar formation compared with exposure to the Diclo solution and to untreated groups. This study also highlighted that Diclo-γ-CD and Diclo-HP-β-CD demonstrated fast healing without scar formation. PMID:29636847

An assessment of the pattern of spontaneous eyeblink activity under the influence of topical ocular anaesthesia.

PubMed

Naase, Taher; Doughty, Michael J; Button, Norman F

2005-04-01

To determine whether there is a change in the pattern of human eyeblink events under topical ocular anaesthesia. Forty male subjects, aged between 19 and 52 years and with no significant ocular surface disease, were recruited. Their spontaneous eyeblink activity, in primary eye gaze position and in silence, was recorded for 5-min periods, before and after instillation of benoxinate 0.4% eyedrops. The surface anaesthesia was confirmed by aesthesiometry. The spontaneous eyeblink rate (SEBR) decreased from 9.1+/-4.0 blinks/min to an average of 5.7+/-3.3 blinks/min, with 37 subjects showing a decreased eyeblink rate under anaesthesia. Three blink patterns were observed before anaesthesia (symmetrical, J-type and I-type) and these were essentially unchanged under anaesthesia. These studies confirm that the SEBR is usually reduced under surface anaesthesia (so is sensitive to exogenous control) but the pattern of the eyeblink activity is unchanged (so is less sensitive to exogenous control). The removal of exogenous stimuli by anaesthesia does not shift the eyeblink pattern to a single type, so indicates endogenous control.

Real-time dose calculation and visualization for the proton therapy of ocular tumours

NASA Astrophysics Data System (ADS)

Pfeiffer, Karsten; Bendl, Rolf

2001-03-01

A new real-time dose calculation and visualization was developed as part of the new 3D treatment planning tool OCTOPUS for proton therapy of ocular tumours within a national research project together with the Hahn-Meitner Institut Berlin. The implementation resolves the common separation between parameter definition, dose calculation and evaluation and allows a direct examination of the expected dose distribution while adjusting the treatment parameters. The new tool allows the therapist to move the desired dose distribution under visual control in 3D to the appropriate place. The visualization of the resulting dose distribution as a 3D surface model, on any 2D slice or on the surface of specified ocular structures is done automatically when adapting parameters during the planning process. In addition, approximate dose volume histograms may be calculated with little extra time. The dose distribution is calculated and visualized in 200 ms with an accuracy of 6% for the 3D isodose surfaces and 8% for other objects. This paper discusses the advantages and limitations of this new approach.

In Vitro/In Vivo Evaluation of Dexamethasone--PAMAM Dendrimer Complexes for Retinal Drug Delivery.

PubMed

Yavuz, Burçin; Pehlivan, Sibel Bozdağ; Vural, İmran; Ünlü, Nurşen

2015-11-01

Current treatment options for diabetic retinopathy (DR) have side effects because of invasive application and topical application does not generally result in therapeutic levels in the target tissue. Therefore, improving the drug delivery to retina, following topical administration, might be a solution to DR treatment problems. The purpose of this study was to investigate the complexation effects of poly(amidoamine) (PAMAM) dendrimers on ocular absorption of dexamethasone (DEX). Using different PAMAM generations, complex formulations were prepared and characterized. Formulations were evaluated in terms of cytotoxicity and cell permeability, as well as ex vivo transport across ocular tissues. The ocular pharmacokinetic properties of DEX formulations were studied in Sprague-Dawley rats following topical and subconjunctival applications, to evaluate the effect of PAMAM on retinal delivery of DEX. Methyl-thiazol-tetrazolium (MTT) assay indicated that all groups resulted in cell viability comparable to DEX solution (87.5%), with the cell viability being the lowest for G3 complex at 73.5%. Transport study results showed that dendrimer complexation increases DEX transport across both cornea and sclera tissues. The results of in vivo studies were also indicated that especially anionic DEX-PAMAM complex formulations have reached higher DEX concentrations in ocular tissues compared with plain DEX suspension. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

The clinical and cellular basis of contact lens-related corneal infections

PubMed Central

Robertson, Danielle M; Cavanagh, H Dwight

2008-01-01

Microbial keratitis (MK) is the most visually devastating complication associated with contact lens wear. Pseudomonas aeruginosa (PA) is highly invasive in the corneal epithelium and is responsible for more than half of the reported cases of contact lens-related MK. To protect against Pseudomonas-mediated MK, the corneal epithelium has evolved overlapping defense mechanisms that function to protect the ocular surface from microbial invasion. Research has shown that contact lens wear disrupts these protective mechanisms through breakdown of normal homeostatic surface renewal as well as damaging the corneal surface, exposing underlying cell membrane receptors that bind and internalize PA through the formation of lipid rafts. Human clinical trials have shown that initial adherence of PA with resulting increased risk for microbial infection is mediated in part by contact lens oxygen transmissibility. Recently, chemical preserved multipurpose solutions (MPS) have been implicated in increasing PA adherence to corneal epithelial cells, in addition to inducing significant levels of toxic staining when used in conjunction with specific silicone hydrogel lenses. This review summarizes what is currently known about the relationship between contact lenses, the corneal epithelium, MPS, and infection. PMID:19277209

Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye.

PubMed

Ramsay, Eva; Del Amo, Eva M; Toropainen, Elisa; Tengvall-Unadike, Unni; Ranta, Veli-Pekka; Urtti, Arto; Ruponen, Marika

2018-07-01

On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70 × 10 -6  cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability. Copyright © 2018 Elsevier B.V. All rights reserved.

Successful single treatment with ziv-aflibercept for existing corneal neovascularization following ocular chemical insult in the rabbit model.

PubMed

Gore, Ariel; Horwitz, Vered; Cohen, Maayan; Gutman, Hila; Cohen, Liat; Gez, Rellie; Kadar, Tamar; Dachir, Shlomit

2018-06-01

To evaluate the efficacy of ziv-aflibercept as a treatment for established corneal neovascularization (NV) and to compare its efficacy to that of bevacizumab following ocular chemical insult of sulfur mustard (SM) in the rabbit model. Chemical SM burn was induced in the right eye of NZW rabbits by vapor exposure. Ziv-aflibercept (2 mg) was applied once to neovascularized eyes by subconjunctival injection while subconjunctival bevacizumab (5 mg) was administered twice a week, for 3 weeks. Non-treated exposed eyes served as a control. A clinical follow-up employed by slit-lamp microscope, was performed up to 12 weeks following exposure and digital photographs of the cornea were taken for measurement of blood vessels length using the image analysis software. Eyes were taken for histological evaluation 2, 4 and 8 weeks following treatment for general morphology and for visualization of NV, using H&E and Masson Trichrome stainings, while conjunctival goblet cell density was determined by PAS staining. Corneal NV developed, starting as early as two weeks after exposure. A single subconjunctival treatment of ziv-aflibercept at 4 weeks post exposure, significantly reduced the extent of existing NV already one week following injection, an effect which lasted for at least 8 weeks following treatment, while NV in the non-treated exposed eyes continued to advance. The extensive reduction in corneal NV in the ziv-aflibercept treated group was confirmed by histological evaluation. Bevacizumab multiple treatment showed a benefit in NV reduction, but to a lesser extent compared to the ziv-aflibercept treatment. Finally, ziv-aflibercept increased the density of conjunctival goblet cells as compared to the exposed non-treated group. Subconjunctival ziv-aflibercept single treatment presented a highly efficient long-term therapeutic benefit in reducing existing corneal NV, following ocular sulfur mustard exposure. These findings show the robust anti-angiogenic efficacy of ziv-aflibercept and demonstrate the advantage of this treatment over the other anti-angiogenic therapies in ameliorating corneal NV and protecting the ocular surface. Copyright © 2018 Elsevier Ltd. All rights reserved.

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

PubMed

Tong, Jiefeng; Hu, Renjian; Zhao, Yingying; Xu, Yang; Zhao, Xiaoying; Jin, Xiuming

2017-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Correlations among ocular surface temperature difference value, the tear meniscus height, Schirmer's test and fluorescein tear film break up time.

PubMed

Su, Tai Yuan; Ho, Wei Ting; Lu, Chien Yi; Chang, Shu Wen; Chiang, Huihua Kenny

2015-04-01

To report the use of a thermographer for measuring ocular surface temperature, and to evaluate the correlation among the obtained temperature difference values (TDVs) and dry eye parameters (tear meniscus height (TMH); Schirmer's test results; fluorescent tear breakup time (FTBUT)). Forty-three participants (age 40.2±14.7 years; range 21-67 years) from Far Eastern Memorial Hospital, Taiwan were recruited for the study. The surface temperature was measured at the centre of the ocular surface for 4 s after blinking. TDV was defined as the change in corneal surface temperature relative to that of the preceding eye opening, where TDV01, TDV02, TDV03, and TDV04 represent the values obtained 1, 2, 3, and 4 s after blinking, respectively. Anterior segment optical coherence tomography (AS-OCT) was employed to measure the lower TMH. Schirmer's test with topical anaesthetic was conducted to measure the basal tear secretion. The FTBUT was recorded using a digital camera. TDV measurement exhibited high reliability (intraclass correlation coefficient=0.91). TDV03 exhibited the highest significance and strongest positive correlation with the TMH (r=0.52, p=0.0003) and Schirmer's test value (r=0.39, p=0.008), whereas the TDV03-FTBUT correlation was non-significant. Age correlated negatively and significantly with the TDV (r= -0.35, p=0.021), TMH (r= -0.33, p=0.031), and Schirmer's test value (r= -0.31, p=0.044). TDV03 remained significantly correlated with the TMH and Schirmer's test value after adjustment for age. The thermographer was effective in capturing temperature changes in the ocular surface. The temperature difference 3 s after blinking appears to be correlated with lower TMH and Schirmer test values. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Identification of SlpB, a Cytotoxic Protease from Serratia marcescens.

PubMed

Shanks, Robert M Q; Stella, Nicholas A; Hunt, Kristin M; Brothers, Kimberly M; Zhang, Liang; Thibodeau, Patrick H

2015-07-01

The Gram-negative bacterium and opportunistic pathogen Serratia marcescens causes ocular infections in healthy individuals. Secreted protease activity was characterized from 44 ocular clinical isolates, and a higher frequency of protease-positive strains was observed among keratitis isolates than among conjunctivitis isolates. A positive correlation between protease activity and cytotoxicity to human corneal epithelial cells in vitro was determined. Deletion of prtS in clinical keratitis isolate K904 reduced, but did not eliminate, cytotoxicity and secreted protease production. This indicated that PrtS is necessary for full cytotoxicity to ocular cells and implied the existence of another secreted protease(s) and cytotoxic factors. Bioinformatic analysis of the S. marcescens Db11 genome revealed three additional open reading frames predicted to code for serralysin-like proteases noted here as slpB, slpC, and slpD. Induced expression of prtS and slpB, but not slpC and slpD, in strain PIC3611 rendered the strain cytotoxic to a lung carcinoma cell line; however, only prtS induction was sufficient for cytotoxicity to a corneal cell line. Strain K904 with deletion of both prtS and slpB genes was defective in secreted protease activity and cytotoxicity to human cell lines. PAGE analysis suggests that SlpB is produced at lower levels than PrtS. Purified SlpB demonstrated calcium-dependent and AprI-inhibited protease activity and cytotoxicity to airway and ocular cell lines in vitro. Lastly, genetic analysis indicated that the type I secretion system gene, lipD, is required for SlpB secretion. These genetic data introduce SlpB as a new cytotoxic protease from S. marcescens. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Identification of SlpB, a Cytotoxic Protease from Serratia marcescens

PubMed Central

Stella, Nicholas A.; Hunt, Kristin M.; Brothers, Kimberly M.; Zhang, Liang; Thibodeau, Patrick H.

2015-01-01

The Gram-negative bacterium and opportunistic pathogen Serratia marcescens causes ocular infections in healthy individuals. Secreted protease activity was characterized from 44 ocular clinical isolates, and a higher frequency of protease-positive strains was observed among keratitis isolates than among conjunctivitis isolates. A positive correlation between protease activity and cytotoxicity to human corneal epithelial cells in vitro was determined. Deletion of prtS in clinical keratitis isolate K904 reduced, but did not eliminate, cytotoxicity and secreted protease production. This indicated that PrtS is necessary for full cytotoxicity to ocular cells and implied the existence of another secreted protease(s) and cytotoxic factors. Bioinformatic analysis of the S. marcescens Db11 genome revealed three additional open reading frames predicted to code for serralysin-like proteases noted here as slpB, slpC, and slpD. Induced expression of prtS and slpB, but not slpC and slpD, in strain PIC3611 rendered the strain cytotoxic to a lung carcinoma cell line; however, only prtS induction was sufficient for cytotoxicity to a corneal cell line. Strain K904 with deletion of both prtS and slpB genes was defective in secreted protease activity and cytotoxicity to human cell lines. PAGE analysis suggests that SlpB is produced at lower levels than PrtS. Purified SlpB demonstrated calcium-dependent and AprI-inhibited protease activity and cytotoxicity to airway and ocular cell lines in vitro. Lastly, genetic analysis indicated that the type I secretion system gene, lipD, is required for SlpB secretion. These genetic data introduce SlpB as a new cytotoxic protease from S. marcescens. PMID:25939509

Inflammation in dry eye.

PubMed

Stern, Michael E; Pflugfelder, Stephen C

2004-04-01

Dry eye is a condition of altered tear composition that results from a diseased or dysfunctional lacrimal functional unit. Evidence suggests that inflammation causes structural alterations and/or functional paralysis of the tear-secreting glands. Changes in tear composition resulting from lacrimal dysfunction, increased evaporation and/or poor clearance have pro-inflammatory effects on the ocular surface. This inflammation is responsible in part for the irritation symptoms, ocular surface epithelial disease, and altered corneal epithelial barrier function in dry eye. Anti-inflammatory therapies for dry eye target one or more of the inflammatory mediators/pathways that have been identified in dry eye.