Impaired healing in an incision wound in corneal stroma in a lumican-null mouse.

PURPOSE: We investigated healing pattern of an incisional wound in corneal stroma of lumican-null (KO) mice. METHODS: C57BL/6 mice (wild-type, WT) and lumican-null (knockout, KO) mice were used. A linear full-thickness incision was produced in one cornea of each mouse. After intervals of healing, the corneas were processed for the following analyses. Histology was employed to measure the distance between each edge of the disrupted Descemet's membrane at the center of the cornea. Immunohistochemistry and real-time RT-PCR were employed to evaluate the expression of wound healing-related components in the tissue. Cultured ocular fibroblasts were obtained from cornea and sclera of WT and KO postnatal day 1 pups. The cells were subjected to examination for cell proliferation and expression of wound healing-related gene products. In vitro gel contraction assay was used to asses cell contractile activity of WT and KO cells. RESULTS: At day 5 of incision, the distance between the disrupted Descemet's membrane was larger in a KO mouse as compared with a WT mouse. Myofibroblast appearance in the wound was suppressed by the loss of lumican. The loss of lumican downregulated TGFß1's effects on mRNA expression of α-smooth muscle actin and collagen Ia1 in cultured ocular fibroblasts. Cell proliferation rate increased in injured stroma, which was further supported by in vitro datum of cell proliferation augmentation by the loss of lumican. Loss of lumican suppressed cell-mediated gel contraction. CONCLUSION: Loss of lumican perturbs the healing of penetrating incision in mouse corneal stroma in association with suppression of myofibroblast generation.

A Glaucoma Patient with an Intraocular Pressure Decrease following Total Gastrectomy and Postoperative Anticancer Treatment.

We herein report a case of glaucoma with an intraocular pressure (IOP) decrease following total gastrectomy (TG) and anticancer treatment for gastric cancer. A 62-year-old male underwent trabeculectomy of the left and right eyes in August 2011 and July 2012, respectively. During the follow-up, IOP of the right eye was 9-12 mmHg (with bimatoprost, dorzolamide, and timolol maleate), and that of the left eye ranged between 14 and 26 mmHg (with bimatoprost, dorzolamide, timolol maleate, and brimonidine tartrate). In December 2014, TG was performed due to gastric cancer. After surgery, the patient received S-1+CDDP, weekly PAC, and CPT-11 therapies. The patient died on March X, 2017. Before TG, the body mass index (BMI) was 29.5 but decreased to 24.8 before the start of the two courses of weekly PAC therapy. IOP of the right eye was 6 mmHg (with bimatoprost), and that of the left eye was 10 mmHg (with bimatoprost, dorzolamide, and brimonidine tartrate), showing decreases. After the initiation of weekly PAC therapy, BMI was approximately 19. IOP of the right eye ranged between 6 and 10 mmHg until the final ophthalmological examination (January 11, 2017), while that of the left eye ranged between 8 and 15 mmHg. In this patient with glaucoma, IOP was not controlled by eye drop treatment, and TG for gastric cancer and postoperative treatment with anticancer drugs resulted in weight loss and a decrease in IOP.

Therapeutic Penetrating Keratoplasty in a Case of Corneal Perforation Caused by Colletotrichum gloeosporioides Infection.

Background: Corneal infection of Colletotrichum gloeosporioides is uncommon and usually limited to the anterior stroma. However, we observed a case of corneal stromal perforation caused by this fungus under a compromised condition. Case: A 73-year-old woman consulted us with a severe corneal ulceration. She was a tangerine orange farmer who suffered from rheumatoid arthritis for more than ten years. Before consultation with us, she received pterygium excision in her right eye. She then developed a corneal ulceration and received topical glucocorticoid therapy upon diagnosis of rheumatoid arthritis-related stromal ulcer in the eye. At the first consultation with us, a corneal ulceration was observed in the inferotemporal area of her right cornea. Biological examination detected a filamentous fungus, Colletotrichum gloeosporioides. Topical and systemic antifungal treatments were not significantly effective. Fourteen days after consultation, the lesion grew worse, leading to stromal perforation, which was treated by therapeutic penetrating keratoplasty using a preserved corneal button. Conclusions: Topical glucocorticoid could accelerate the growth of Colletotrichum gloeosporioides before diagnosis, even though the primary cause of corneal ulceration development might be rheumatoid arthritis.

[Effects of Benzalkonium Chloride in Ophthalmic Eyedrop Medications on Corneal Epithelium].

Eyedrops often contain additives other than active pharmaceutical ingredients, such as preservatives. The most frequently used preservative is benzalkonium chloride (BAC). When the ocular surface is exposed to eyedrops, the active pharmaceutical ingredients and additives can cause corneal epithelial disorder. Particularly in clinical settings, there is great interest in corneal epithelial disorders resulting from the use of glaucoma eyedrops, which is inevitable when instilled for a long period of time after the onset of disease. At the authors' institute, glaucoma is treated with consideration of reducing corneal epithelial disorder while ensuring the effect of lowering intraocular pressure by the appropriate choice of eyedrops. In this review, we show the examples of the retrospective studies. Sodium hyaluronate eyedrops are prescribed for corneal epithelial disorders such as superficial punctate keratitis associated with dry eye. Prescribable concentrations of sodium hyaluronate in Japan are 0.1% or 0.3%, and the 0.3% formulation does not contain BAC. The authors' study showed that 0.3% sodium hyaluronate pretreatment reduced the cytotoxicity of BAC in cultured corneal epithelial cells, whereas an in vivo study in mice showed that a 0.3% sodium hyaluronate instillation was suggested and that the drug may enhance the cytotoxicity of separately administered BAC. It is suggested that sodium hyaluronate prolonged the retention of BAC on the ocular surface. However, there have been no reports of this problem in the clinical setting. It is important for ophthalmologists to understand the properties of additives other than the active pharmaceutical ingredients in eyedrops.

Long-term intraocular pressure after switching a combination ophthalmic medication of ß-blocker/prostaglandin.

PURPOSE: We examined intraocular pressure (IOP)-reducing effects 12 months after switching timolol maleate/travoprost combination ophthalmic solution in one bottle (TM/TR-COMBI-SOL) to carteolol hydrochloride/latanoprost combination ophthalmic solution in one bottle (CR/LT-COMBI-SOL). CASES: The participants included 25 patients (25 eyes) who could be followed up for 12 months after a switch from TM/TR-COMBI-SOL to CR/LT-COMBI-SOL in Saiseikai Arida Hospital between March 1, 2017, and August 31, 2018. They consisted of patients in whom antiglaucoma eye drop other than TM/TR-COMBI-SOL had not been used (monotherapy group, 12 patients [12 eyes], 12.8 ± 3.0 mmHg) and those in whom antiglaucoma eye drop other than TM/TR-COMBI-SOL had been concomitantly used (multitherapy group, 13 patients [13 eyes], 13.8 ± 2.4 mmHg). We excluded patients in whom drugs for glaucoma were changed or added during the follow-up and those who underwent intraocular surgery. MATERIALS AND METHODS: We retrospectively and statistically examined the IOP before eye drop switching and after 1, 6, and 12 months, using the paired t-test. RESULTS: The IOPs 1 month after eye drop switching in the monotherapy group and multitherapy group were 12.5 ± 3.3 and 13.8 ± 2.5 mmHg, respectively. The values after 6 months were 13.5 ± 3.0 and 11.5 ± 2.7 mmHg, respectively. Those after 12 months were 12.8 ± 2.7 and 11.7 ± 2.5 mmHg, respectively. In the monotherapy group, there was no significant difference during the follow-up period. In the multitherapy group, there were significant decreases in comparison with the preswitching value after 6 and 12 months (P < 0.05, respectively). CONCLUSION: The IOP-reducing effects of CR/LT-COMBI-SOL were similar to those of TM/TR-COMBI-SOL. However, the effects may be enhanced after switching from TM/TR-COMBI-SOL in patients receiving multitherapy.

A Case of Repeating Transient Increase in Intraocular Pressure by Instability of an Intraocular Lens Implanted in the Capsular Bag.

We observed repeated episodes of rapid increases in intraocular pressure (IOP) considered to be caused by an in-the-bag intraocular lens (IOL) instability in a patient with an implanted IOL. As acute glaucoma attack-like increase in IOP was noted in the left eye on November 8, she was admitted to Wakayama Medical University Hospital. The findings at the first examination included an IOP of 62 mm Hg, instability of a PMMA one-piece IOL, shallow anterior chamber, narrow angle, moderate mydriasis, and loss of pupillary light reaction in the left avitreous eye. On November 15, a 6-mm Hg increase in IOP was observed during 60-min dark room prone provocative testing. After the first examination, the patient perceived pain and reduced visual acuity of the left eye and emergently consulted our hospital twice. Despite miosis, normalization of the anterior chamber depth and IOP with widening of the angle were achieved by resting in the supine position. These episodes were thought to be caused by instability and anterior shift of the IOL. On January 17, 2018, suture fixation of the in-the-bag IOL was performed. The IOL was fixed by transscleral suturing of the bilateral supporting parts to the sclera. Recurrence of sudden ophthalmalgia, instability of the in-the-bag IOL, and an increase in IOP have not been observed for 1 year after surgical treatment. Instability of an in-the-bag IOL caused repeated acute angle-closure glaucoma-like attacks. The situation was well treated by suturing and fixing the haptics of IOL to the sclera.

Effects of a prostaglandin F2alpha derivative glaucoma drug on EGF expression and E-cadherin expression in a corneal epithelial cell line.

Purpose: We examined the effects of travoprost on cell proliferation-related signals and E-cadherin expression in vitro and in situ in order to obtain evidence to support the hypothesis that topical travoprost impairs the integrity of the corneal epithelium.Methods: A human corneal epithelial cell culture was treated with travoprost (0.4 mg/ml) and/or PD168393 (an EGF receptor inhibitor, 10 µM). The culture was then processed for cell proliferation, an mRNA expression analysis of epidermal growth factor (EGF) and E-cadherin, and protein expression analysis of E-cadherin by immunocytochemistry and Western blotting. The eyes of C57/BL6 mice were incubated in serum-free medium plus travoprost (0.4 mg/ml) and/or PD168393 (10 µM). After being cultured for 24 h, the expression patterns of phospho-EGFR, phospho-ERK, E-cadherin, and Ki67 were immunohistochemically examined in paraffin sections.Results: The addition of travoprost up-regulated EGF mRNA expression and cell proliferation in the corneal epithelial cell culture, and this was cancelled by the addition of PD168393. This FP agonist also decreased E-cadherin expression levels in the cell-cell contact zone, and this was cancelled by the addition of PD168393. In the organ culture, the addition of travoprost to the medium up-regulated the expression of phospho-EGFR and phospho-ERK as well as cell proliferation, and down-regulated the expression of E-cadherin in the corneal epithelium, particularly in basal cells, whereas PD168393 reversed these effects.Conclusions: Travoprost activates epithelial cell proliferation by up-regulating an EGF-related signal in association with the suppression of E-cadherin localization in the cell-cell contact zone. Modulation of the EGF signal may be a strategy to minimize the negative impact of this mitogen on reformation of corneal barrier function during epithelial renewal.

A Case of Solitary Nonvascularized Corneal Epithelial Dysplasia.

Background. Epithelial dysplasia is categorized as conjunctival/corneal intraepithelial neoplasia which is a precancerous lesion. The lesion is usually developed at the limbal region and grows towards central cornea in association with neovascularization into the lesion. Here, we report a case of isolated nonvascularized corneal epithelial dysplasia surrounded by normal corneal epithelium with immune histochemical finding of ocular surface tissues cytokeratins, for example, keratin 13 and keratin 12. Case Presentation. A 76-year-old man consulted us for visual disturbance with localized opacification of the corneal epithelium in his left eye. His visual acuity was 20/20 and 20/200 in his right and left eye, respectively. Slit lamp examination showed a whitish plaque-like lesion at the center of his left corneal epithelium. No vascular invasion to the lesion was found. The lesion was surgically removed and subjected to histopathological examination and diagnosed as epithelial dysplasia. Amyloidosis was excluded by direct fast scarlet 4BS (DFS) staining. Immunohistochemistry showed that the dysplastic epithelial cells express keratin 13 and vimentin, but not keratin 12, indicating that the neoplastic epithelial cells lacked corneal-type epithelium differentiation. Conclusions. The lesion was diagnosed as nonvascularized epithelial dysplasia of ocular surface. Etiology of the lesion is not known.

A patient with corneal epithelial disorder that developed after administration of a latanoprost generic, but not a brand-name drug, eye drop.

Background. We report a patient who developed corneal epithelial disorder repeatedly after changing the prescription from Xalatan eye drops (Pfizer Inc.) to Latanoprost eye drops (Kaken Pharmaceutical Co., Ltd.), both containing 0.005% latanoprost. Case Report. An 88-year-old male with glaucoma had been treated with Timoptol eye drops and Xalatan eye drops for a few years. While he stayed in a health care facility for the elderly, Xalatan eye drops was changed to Latanoprost eye drops usage, and eye pain developed on the day of this change. On the next day, he visited our department, and corneal epithelial disorder was observed. The drops were discontinued, and the corneal epithelial disorder healed after 2 days. Twenty days after the first consultation, Xalatan eye drops and Latanoprost eye drops were resumed by a physician of internal medicine in the health care facility, but eye pain developed again. After discontinuation of the two drugs, Xalatan eye drops usage was resumed the next day, but no corneal epithelial disorder was observed thereafter. Conclusions. This clinical history strongly suggested the association between a generic drug, Latanoprost eye drops, and the development of corneal epithelial disorder.