Localized light chain amyloidosis involving the lacrimal sac: A case report.

Amyloidosis involving the lacrimal sac is extremely rare. In this study, we demonstrated a rare case of localized light chain amyloidosis in the lacrimal sac region. The lacrimal sac lesion presented as infiltrative with bony erosion. Given the slow growth of the lesion and the absence of a blood flow signal inside, we concluded that the lesion was less likely to be malignant. Complete removal of the lacrimal sac lesion combined with simultaneous lacrimal passage reconstruction was performed. The diagnosis of light chain amyloidosis was confirmed by histology. The surgical results were favorable, and no recurrence was observed over one-year follow-up. Our case report enriches the understanding of amyloid deposition in the ocular adnexa.

Newly recognized orbital malformations in kabuki syndrome: A case report.

Kabuki syndrome (KS) is a rare congenital disorder with distinctive characteristics. Herein, we describe a KS patient carrying a novel mutation in the KMT2D gene, c.11785C > T (p.Gln3929*). The patient presented with typical eyelid deformities, including eversion of the lateral lower eyelids, long palpebral fissures, hypertelorism, and medial epicanthus. Orbital computed tomography revealed orbital bone malformation with temporally and inferiorly displaced zygomatic bone. The bilateral orbits were shallow with an enlarged angle between the lateral walls. Zygomatic and maxillary bone dysplasia were also observed. Orbital bone anomalies are thought to be one of the characteristics of KS.

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway.

Purpose: To evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis. Methods: OFs were cultured from orbital connective tissues obtained from patients with TED (n = 10) and healthy controls (n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by RNA sequencing. Results: The mRNA and protein levels of SOX9 were significantly higher in OFs cultured from patients with TED than those from healthy controls. Extracellular matrix-related genes were down-regulated by SOX9 knockdown and up-regulated by SOX9 overexpression in TED-OFs. SOX9 knockdown significantly decrease the contraction and the antiapoptotic ability of OFs, whereas the overexpression of SOX9 increased the ability of transformation, migration, and proliferation of OFs. SOX9 knockdown suppressed the expression of phosphorylated ERK1/2, whereas its overexpression showed the opposite effect. Epidermal growth factor receptor (EGFR) is one of the notably down-regulated genes screened out by RNA sequencing. Chromatin immunoprecipitation-qPCR demonstrated SOX9 binding to the EGFR promoter. Conclusions: A high expression of SOX9 was found in TED-OFs. SOX9 can activate OFs via MAPK/ERK1/2 signaling pathway, which in turn promotes proliferation and differentiation of OFs. EGFR was a downstream target gene of SOX9. SOX9/EGFR can be considered as therapeutic targets for the treatment of orbital fibrosis in TED.

Melatonin Alleviates Retinal Ischemia-Reperfusion Injury by Inhibiting p53-Mediated Ferroptosis.

Retinal ischemia-reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR-induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12-lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT-ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53-mediated ferroptosis. These findings indicate that MT is a retina-specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection.

Lutein targeting orbital fibroblasts attenuates fibrotic and inflammatory effects in thyroid-associated ophthalmopathy.

Lutein (LU) is a carotenoid that has recently been implicated in multiple roles in fibrosis, inflammation, and oxidative stress. Thyroid-associated ophthalmopathy (TAO) is particularly relevant to these pathological changes. We thus aim to probe the potential therapeutic effects of TAO in an in vitro model. We used LU pre-treating OFs derived from patients with TAO or not, then treated with TGF-ß1(or IL-1ß)to induce fibrosis (or inflammation). We analyzed the different expressions of related genes and proteins, and the molecular mechanism pathway on TAO OFs was screened by RNA sequencing, which is identified in vitro. We found that LU attenuates fibrotic and inflammatory effects in TAO. LU inhibited ACTA2, COL1A1, FN1, and CTGF mRNA expression and suppressed α-SMA, and FN1 protein expression induced by TGF-ß1. Besides, LU suppressed OFs migration. Besides, it is shown that LU suppressed inflammation-related genes, such as IL-6, IL-8, CXCL1, and MCP-1. Moreover, LU inhibited oxidative stress induced by IL-1ß, which is analyzed by DHE fluorescent probe staining. RNA sequencing suggested ERK/AP-1 pathway may be the molecular mechanism of LU protective effect on TAO, which is identified by RT-qPCR and western-blot. In summary, this study provides the first evidence that LU significantly attenuates the pathogenic manifestations of TAO by inhibiting the expression of fibrotic and inflammation-related genes and ROS produced by OFs. These data suggested that LU may be a potential medicine for TAO.

The Recurrence of Ptosis after Correction Surgery Is Associated with Refractive Error.

Background and objectives: Previous studies on ptosis recurrence after correction surgery have tended to focus on postoperative complications, surgical methods and suspension materials, few have mentioned refractive error. This research is to investigate the potential relation between refractive error and recurrence after correction surgery in pediatric patients with simple congenital ptosis. Materials and Methods: We conducted a retrospective analysis of data from patients with simple congenital ptosis who were treated at Zhongshan Ophthalmic Center (ZOC) between 2017 and 2020. In total, 111 eyelids of 85 patients without surgery-related complications who underwent frontalis muscle flap suspension (FMFS) for simple congenital ptosis were included. Postoperative changes in eyelid height were assessed. Cycloplegic refraction was assessed before surgery and during the follow-up period (every 3 months after surgery). Recurrence in the postoperative period was defined as a marginal reflex distance 1 (MRD1) of <1 mm. Results: There were 16 recurrence and 69 non-recurrence cases, with no statistically significant differences, in terms of patient age at the time of surgery, patient sex, or preoperative MRD1, between the recurrence and non-recurrence groups. The postoperative cylindrical diopter (adjusted odds ratio [OR] = 0.432, p = 0.005), laterality (adjusted OR = 0.202, p = 0.006), and preoperative MRD1 (adjusted OR = 0.617, p = 0.019) were associated with ptosis recurrence after surgery. Differences between the recurrence and non-recurrence groups in spherical diopter and spherical equivalent (SE) before and after surgery were not statistically significant. In addition, preoperative refractive error and postoperative spherical diopter were not significantly associated with ptosis recurrence after correction surgery. Conclusions: Ptosis recurrence after FMFS in pediatric cases of congenital ptosis is associated with refractive error. Timely refractive correction and amblyopia treatment may help to reduce ptosis recurrence.

Missense Mutations in MAB21L1: Causation of Novel Autosomal Dominant Ocular BAMD Syndrome.

Purpose: Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous pathogenic variants have been suspected to cause autosomal dominant (AD) microphthalmia and aniridia in eight families. This study aimed to report an AD ocular syndrome (blepharophimosis plus anterior segment and macular dysgenesis [BAMD]) syndrome based on clinical and genetic findings from patients with monoallelic MAB21L1 pathogenic variants in our cohort and reported cases. Methods: Potential pathogenic variants in MAB21L1 were detected from a large in-house exome sequencing dataset. Ocular phenotypes of the patients with potential pathogenic variants in MAB21L1 were summarized, and the genotype-phenotype correlation was analyzed through a comprehensive literature review. Results: Three heterozygous missense variants in MAB21L1, predicted to be damaging, were detected in 5 unrelated families, including c.152G>T in 2, c.152G>A in 2, and c.155T>G in one. All were absent from gnomAD. The variants were de novo in two families, transmitted from affected parents to offspring in two families, and with an unknown origin in the other family, demonstrating strong evidence of AD inheritance. All patients revealed similar BAMD phenotypes, including blepharophimosis, anterior segment dysgenesis, and macular dysgenesis. Genotype-phenotype analysis suggested that patients with monoallelic MAB21L1 missense variants had only ocular anomalies (BAMD), whereas patients with biallelic variants presented both ocular and extraocular symptoms. Conclusions: Heterozygous pathogenic variants in MAB21L1 account for a new AD BAMD syndrome, which is completely different from COFG caused by homozygous variants in MAB21L1. Nucleotide c.152 is likely a mutation hot spot, and the encoded residue of p.Arg51 might be critical for MAB21L1.

Early detection of visual impairment in young children using a smartphone-based deep learning system.

Early detection of visual impairment is crucial but is frequently missed in young children, who are capable of only limited cooperation with standard vision tests. Although certain features of visually impaired children, such as facial appearance and ocular movements, can assist ophthalmic practice, applying these features to real-world screening remains challenging. Here, we present a mobile health (mHealth) system, the smartphone-based Apollo Infant Sight (AIS), which identifies visually impaired children with any of 16 ophthalmic disorders by recording and analyzing their gazing behaviors and facial features under visual stimuli. Videos from 3,652 children (≤48 months in age; 54.5% boys) were prospectively collected to develop and validate this system. For detecting visual impairment, AIS achieved an area under the receiver operating curve (AUC) of 0.940 in an internal validation set and an AUC of 0.843 in an external validation set collected in multiple ophthalmology clinics across China. In a further test of AIS for at-home implementation by untrained parents or caregivers using their smartphones, the system was able to adapt to different testing conditions and achieved an AUC of 0.859. This mHealth system has the potential to be used by healthcare professionals, parents and caregivers for identifying young children with visual impairment across a wide range of ophthalmic disorders.

Intraorbital self-inflating hydrogel expander implantation with a modified technique in congenital microphthalmia.

PURPOSE: To investigate the long-term outcomes of intraorbital self-inflating hydrogel expander implantation with optic nerve transection in children with congenital microphthalmia. METHODS: The medical records of unilaterally blind microphthalmic pediatric patients undergoing intraconal hydrogel expander implantation with optic nerve transection were reviewed retrospectively. For each patient, the microphthalmic eye was preserved. The orbital volume and globe volume were measured and analyzed based on computed tomography scans taken preoperatively and 36 months postoperatively. The palpebral length was measured between the medial and lateral canthus at every follow-up. Surgical complications were also recorded. RESULTS: Twelve patients were included (median age, 44.25 ± 17.5 months). At 36 months postoperatively, the microphthalmic and contralateral orbital volumes increased by 3.07 ± 0.77 ml and 2.03 ± 0.67 ml, respectively. The mean microphthalmic/contralateral ratio (MCR) of the orbital volume increased significantly from 76.60% ± 5.46% to 83.81% ± 5.41% (P < 0.001). The microphthalmic palpebral length increased by 6.17 ± 1.85 mm, whereas the contralateral palpebral length increased by 2.67 ± 1.44 mm. Significant changes were observed in the palpebral length MCR (68.00% ± 4.83% vs 85.07% ± 3.87%; P < 0.001). There was no significant change in the microphthalmic globe volume at 36 months postoperatively (P = 0.215). For the fellow eye, the globe volume increased significantly by 0.53 ± 0.34 ml (P < 0.001). During the follow-up period, 2 patients developed a sunken prosthesis. One patient had difficulty opening the eye after wearing the conformer. There were no cases of expander rejection or extrusion. CONCLUSIONS: In this small cohort of patients with congenital microphthalmia, intraorbital self-expanding hydrogel expander implantation with optic nerve transection led to excellent osseous and eyelid growth throughout the 36-month follow-up period.

Melatonin exerts anti-angiogenic and anti-inflammatory effects in alkali-burned corneas.

Background: Corneal neovascularization (CNV) caused by alkali burn injury is tightly associated with an inflammatory reaction and can lead to vision loss. Melatonin is involved in anti-inflammation and anti-angiogenesis, but its role in CNV has not yet been investigated. Methods: We induced CNV using sodium hydroxide (NaOH) and compared the reactions of vehicle control and melatonin-treated male C57BL/6 mice at 7 and 14 days following the corneal burn. The infiltration of inflammatory cells and the expression of proangiogenic factors, chemokines, and inflammation-related molecules were quantified via immunohistochemical (IHC) analysis and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), respectively. Murine peritoneal macrophages were used in vitro to further verify the effect of melatonin in inflammatory CNV. Results: Compared with the vehicle control mice, the melatonin-treated mice showed significant inhibition of angiogenesis and reduction of corneal epithelial defects in alkali-burned corneas. Concomitantly, the infiltration of inflammatory cells and F4/80+ cells were dramatically reduced after melatonin treatment. The messenger RNA (mRNA) expression of proangiogenic factors [vascular endothelial growth factors (VEGF) and matrix metalloproteinase-9 (MMP-9)], monocyte chemotactic protein-1 (MCP-1), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) and IL-6] were down-regulated in the melatonin-treated mice. Moreover, melatonin inhibited the expression of these factors in murine peritoneal macrophages. Conclusions: Melatonin inhibits the neovascular and inflammatory responses in corneal alkali burn injury, suggesting that it may be a potential therapy for CNV.

IL-11 Is Elevated and Drives the Profibrotic Phenotype Transition of Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy.

Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient's clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. IL-11 levels in serum and orbital connective tissues were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-ß1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-ß1 and IL-1ß. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by inducing the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.

Finite Element Analysis of 2- and 3-Point Internal Fixation Methods for the Treatment of Zygomaticomaxillary Complex Fracture.

Open reduction followed by internal fixation (ORIF) has been regarded as the most effective technique for surgical repair of zygomaticomaxillary complex (ZMC) fractures. However, the ideal internal fixation method to achieve stable reduction remains controversial. This research aims to assess and compare the stability of the 2- and 3-point screw-plate fixation methods using finite element method (FEM). Based on computed tomography (CT), the finite element models of 2-point (ZFS + IOR) and 3-point (ZFS + IOR + ZMB) fixation for isolated displaced ZMC fracture were reconstructed. The force of 120 N was applied to the models to simulate the masseter muscle strength. The maximum stress and displacement of the 2 models were measured to compare the stability. Two geometrically accurate and finite element models were reconstructed successfully. In both the 2- and 3-point fixation models, the maximum stress was significantly lower than the mechanical properties of pure titanium and titanium alloys and the maximum displacement was ≤0.1 mm. The results of this study suggested that both 2- and 3-point fixation of isolated displaced ZMC fractures provide good stability. The FEM innovatively applied in this study can not only show the biomechanical properties of the orbital skeleton and masseter muscle but also assess the stability of the two fixation methods and provide a theoretical reference. This study verifies the effectiveness of 2-point fixation and combined with the clinical benefits of reduced incisions, shorter operative time and lower cost, make this an attractive method.