JNK and p38 Inhibitors Prevent Transforming Growth Factor-ß1-Induced Myofibroblast Transdifferentiation in Human Graves' Orbital Fibroblasts.

Transforming growth factor-ß1 (TGF-ß1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves' ophthalmopathy (GO). However, the signaling pathways through which TGF-ß1 activates Graves' orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-ß1-induced myofibroblast transdifferentiation in human Graves' orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-ß1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-ß1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-ß1 could induce myofibroblast transdifferentiation in human Graves' orbital fibroblasts through the p38 and JNK pathways.

Visual Acuity Impairment from Inflammatory Isolated Sphenoid Sinus Disease.

BACKGROUND/AIM: To investigate the treatment outcomes and determinants of prognosis in patients experiencing visual acuity (VA) deterioration due to inflammatory isolated sphenoid sinus disease (ISSD) who underwent endonasal endoscopic surgery (EES). PATIENTS AND METHODS: Thirteen patients with 14 lesions treated with EES between March 2010 and April 2022 were included. Evaluation included improvements in VA using the logarithm of the minimum angle of resolution (LogMAR) scale, resolution rates of associated symptoms, and identification of factors predicting VA recovery. A literature review was conducted to assess the outcomes for ISSD-related VA impairments. RESULTS: The most common etiology is mycetoma (n=5), followed by an equal representation of mucocele and sphenoiditis (n=4). The mean interval from symptom onset to intervention was 4.7 months, with an average follow-up duration of 14.4 months. Seven eyes exhibited preoperative VA of 2.1 LogMAR or worse, with diplopia/ptosis (n=8) and headache (n=5) being the predominant co-occurring symptoms. After surgery, all ancillary symptoms improved, with an overall VA recovery rate of 87.5% (improvement more than 0.2 logMAR units). Mucocele exhibited the best improvements, whereas sphenoiditis showed the least progress (p=0.021). Poor baseline VA (p=0.026) and combined diplopia/ptosis (p=0.029) were identified as negative prognostic factors for VA recovery. CONCLUSION: Our findings suggest a favorable prognosis for VA recovery following EES in patients with inflammatory ISSDs, with response variations based on disease entity. However, further research is needed to personalize therapeutic strategies for enhanced outcomes.

Plug-related canaliculitis: a rare or underdiagnosed disease?

CLINICAL RELEVANCE: Conjunctivitis, chalazion and blepharitis are routinely managed by optometrists. However, it is especially important to consider the diagnosis of canaliculitis in patients with chronic or recurrent conditions. BACKGROUND: This study aimed to report the clinical features, radiological findings and treatment outcomes in patients with plug-related canaliculitis. METHODS: This retrospective study included patients with canaliculitis secondary to plug insertion between 2007 and 2020. All data regarding epidemiological characteristics, clinical presentation, isolated microorganisms, computed tomography imaging findings, treatment, and outcomes were analysed. RESULTS: A total of 20 plug-related canaliculitis from 19 patients (18.3%) among all 109 cases of canaliculitis were identified. All patients with plug-related canaliculitis were females with a past history of lacrimal plug insertion for dry eye (mean age: 58.2 years). Most patients were initially treated as conjunctivitis with the mean time lapse to a diagnosis of 5.2 months. The average time from plug insertion to onset of symptoms was 5.1 years. Eighteen patients underwent canaliculotomy, and one patient received lacrimal irrigation. Plugs were identified in 18 cases, with SmartPlug in 13 cases (72%), followed by EaglePlugTM (two cases), Herrick Lacrimal Plug (two cases), and migrated FCI Painless Plug (1 case). Cultures of discharge, concretions, and/or infected plugs mostly revealed Pseudomonas aeruginosa (42%). Orbital computed tomography in four cases with SmartPlug revealed central radiolucency with surrounding soft-tissue enhancement. No recurrent canaliculitis was observed throughout a mean follow-up period of 13.7 months. No patient needed re-plugging after canaliculotomy and plug removal, with only one required additional lubricants for recurrent dry eye. CONCLUSION: Plug-related canaliculitis is often underdiagnosed due to late onset and similar symptoms to common ocular diseases. Awareness of plug insertion history as well as meticulous removal of the plug, concretion and/or granulation tissue is important for early diagnosis and to ensure a good outcome.

Effect of Pirfenidone on TGF-ß1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves' Ophthalmopathy.

Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-ß1 (TGF-ß1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves' ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 µg/mL, respectively) for one hour followed by TGF-ß1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-ß1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-ß1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-ß1 pathways. These findings suggest that pirfenidone modulates TGF-ß1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-ß1.

The Role of Oxidative Stress and Therapeutic Potential of Antioxidants in Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO) is the most common extrathyroidal manifestation of Graves' disease. It is characterized initially by an inflammatory process, followed by tissue remodeling and fibrosis, leading to proptosis, exposure keratopathy, ocular motility limitation, and compressive optic neuropathy. The pathogenic mechanism is complex and multifactorial. Accumulating evidence suggests the involvement of oxidative stress in the pathogenesis of GO. Cigarette smoking, a major risk factor for GO, has been shown to induce reactive oxygen species (ROS) generation and oxidative damage in GO orbital fibroblasts. In addition, an elevation in ROS and antioxidant enzymes is observed in tears, blood, and urine, as well as orbital fibroadipose tissues and fibroblasts from GO patients. In vitro and in vivo studies have examined the efficacy of various antioxidant supplements for GO. These findings suggest a therapeutic role of antioxidants in GO patients. This review summarizes the current understanding of oxidative stress in the pathogenesis and potential antioxidants for the treatment of GO.

The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center.

Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13-58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

Optic Disc and Macular Vessel Density Measured by Optical Coherence Tomography Angiography in Open-Angle and Angle-Closure Glaucoma.

There is distinct pathogenesis between primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Although elevated intraocular pressure (IOP) is the major risk factor for glaucoma, non-IOP risk factors such as vascular abnormalities and lower systolic/diastolic perfusion pressure may play a role in the pathogenic process. This study aimed to compare the vessel density (VD) in the optic disc and macula using optical coherence tomography angiography (OCTA) between POAG and PACG eyes. Thirty-two POAG eyes, 30 PACG eyes, and 39 control eyes were included. All the optic disc VD parameters except the inside disc VD were significantly lower in glaucomatous eyes than in control eyes. Compared with PACG eyes, only the inferior temporal peripapillary VD was significantly lower in POAG eyes. The parafoveal VD was significantly lower in each quadrant in glaucomatous eyes than in control eyes. The central macular and parafoveal VD did not differ between POAG and PACG eyes. In conclusion, the inferior temporal peripapillary VD was significantly reduced in POAG eyes compared with PACG eyes, while PACG eyes showed a more evenly distributed reduction in the peripapillary VD. The distinct patterns of VD change may be associated with the different pathogenesis between POAG and PACG.

Predictive factors of visual outcome in posterior segment intraocular foreign body.

BACKGROUND: To identify the predictive factors for visual outcomes of patients with posterior segment intraocular foreign body (IOFB) after open-globe injury. METHODS: A retrospective, interventional study was conducted to evaluate consecutive patients with retained posterior segment IOFB who underwent vitrectomy over a 10-year period from 2007 to 2016. Multivariate linear regression analysis was used to identify the potential predictive factors for final visual outcomes. RESULTS: Forty-two patients were evaluated, with predominantly males (97.6%) and mean age 37.21 years. Hammering on metal (47.62%) was the major mechanism of injury. The majority of foreign bodies were metallic (95.24%) with a mean dimension of 4.3 mm. Twenty-four (57.14%) patients initially presented with a Snellen visual acuity <6/60. After surgery, 19 (45.24%) eyes had final visual outcomes of 6/12 or better; however, visual outcomes worse than 6/60 were documented in 17 (40.48%) eyes. Multivariate linear regression analysis revealed that the occurrence of retinal detachment (RD; p<0.01) and larger IOFB dimension (p=0.02) independently predicted worse final visual outcomes after adjusting for age and initial VA. Eyes with entry wounds located posteriorly into the sclera significantly increased the risk of RD compared to eyes with entry wounds involving cornea only (p=0.03). There was no association between time interval for IOFB removal and development of endophthalmitis. CONCLUSION: RD and larger IOFB dimension are significant predictive factors associated with worse final visual outcomes. Increased time to IOFB removal is not associated with either a higher risk of endophthalmitis or worse visual outcomes.

Rapid resolution of stromal keratitis with the assistance of oral voriconazole in resistant acanthamoeba keratitis.

Acanthamoeba keratitis (AK) is an unusual infectious disease of the cornea which sometimes leads to blindness. We report the experience of adding oral voriconazole in conjunction with topical antiacanthamoebic drops to treat refractory AK. A 20-year-old girl experienced a deep stromal keratitis with large epithelial defect in the left eye, suspected as AK. The initial best-corrected visual acuity (BCVA) of the eye was counting finger. She received topical chlorhexidine 0.02% and voriconazole 1% during the first 14 days but in vain. Oral voriconazole was administered and resulted in a rapid regression of the lesion. A total resolution was achieved after 2 weeks of triple combination therapy. The BCVA of the left eye finally achieved 20/20 at 6-month follow-up. Although oral voriconazole was seldom used in treating acute AK, the additional use of oral voriconazole combined with topical antiacanthamoebic drugs may help to achieve a successful treatment effect in refractory stromal AK.