Cu/Gd co-doped hydroxyapatite/poly lactic-co-glycolic acid composites enhance MRI imaging and bone defect regeneration.

Background: The hydroxyapatite (HA)/poly(lactide-co-glycolide) acid (PLGA) composite material is a widely used orthopedic implant due to its excellent biocompatibility and plasticity. Recent advancements in cation doping have expanded its potential biological applications. However, conventional HA/PLGA composites are not visible under X-rays post-implantation and have limited osteogenic induction capabilities. Copper (Cu) is known to regulate osteoblast proliferation and differentiation, while gadolinium (Gd) can significantly enhance the magnetic resonance imaging (MRI) capabilities of materials. Methods: This study aimed to investigate whether incorporating Cu and Gd into an HA/PLGA composite could enhance the osteogenic properties, in vivo bone defect repair, and MRI characteristics. We prepared a Cu/Gd@HA/PLGA composite and assessed its performance. Results: Material characterization confirmed that Cu/Gd@HA retained the morphology and crystal structure of HA. The Cu/Gd@HA/PLGA composite exhibited excellent nuclear magnetic imaging capabilities, porosity, and hydrophilicity, which are conducive to cell adhesion and implant detection. In vitro experiments demonstrated that the Cu/Gd@HA/PLGA composite enhanced the proliferation, differentiation, and adhesion of MC3T3-E1 cells, and upregulated COL-1 and BMP-2 expression at both gene and protein levels. In vivo studies showed that the Cu/Gd@HA/PLGA composite maintained strong T1-weighted MRI signals and significantly improved the bone defect healing rate in rats. Conclusion: These findings indicate that the Cu/Gd@HA/PLGA composites significantly enhance T1-weighted MRI capabilities, promote osteoblast proliferation and differentiation in vitro, and accelerate bone defect healing in vivo.

Medical, Environmental, and Social Determinants Associated With Periocular Cutaneous Malignancies in the United States Using the All of Us National Database.

OBJECTIVE: To identify common factors associated with periocular cutaneous malignancies using the National Institutes of Health (NIH) All of Us database. METHODOLOGY: In this case-control study, we extracted electronic health records and sociodemographic data for 385 cases of periocular cutaneous malignancies from the All of Us nationwide database. Controls (N = 1540) were matched to the demographic characteristics of the 2020 United States Census. Bivariate analyses and multivariable logistic regression determined variables significantly associated with increased odds of periocular cutaneous malignancies. We analyzed medical, environmental, and social determinants to evaluate which factors were associated with increased odds of periocular cutaneous malignancies. RESULTS: Among the cases, the mean (standard deviation) age was 66.8 (11.2) years at the time of diagnosis. The majority were male (207, 54%) and white (361, 94%). Periocular cutaneous malignancy was significantly more likely among individuals with high sun exposure (odds ratio [OR] 14.79, 95% confidence interval [CI] 3.35-85.73, P = 0.001), those identifying as white race (OR 3.88, 95% CI 1.06-25.33, P = 0.079), and those with higher socioeconomic status, including higher annual income (OR 1.35, 95% CI 1.25-1.46, P < 0.001). CONCLUSIONS: This study demonstrates similar risk factors for periocular cutaneous malignancies, echoing prior research that showed increased associations with lighter-pigmented skin and higher socioeconomic status. It also sheds light on the positive impact of physician surveillance and health utilization factors in the early detection and treatment of these malignancies, aspects less explored in prior analyses.

The utility of orbital imaging in the evaluation of orbital disease.

PURPOSE: This study investigates the accuracy of either computerized tomography (CT) or magnetic resonance imaging (MRI) for the evaluation of various orbital diseases. METHODS: We collected 126 CT scans and 65 MRI scans from 144 subjects and asked two radiologists to interpret the images without clinical information. Images included 14 with a clinical diagnosis of orbital infection, 144 with orbital inflammation, and 33 with orbital neoplasm. The inflammatory diseases included thyroid eye disease (TED, n = 69), non-specific orbital inflammation (NSOI, n = 44), IgG4-related disease (IgG4-RD, n = 15), sarcoidosis (Sarcoid, n = 9), granulomatosis with polyangiitis (GPA, n = 5), and Erdheim-Chester disease (ECD, n = 2). RESULTS: The balanced accuracy (BA) for the two radiologists ranged from 0.87 to 0.90 for cellulitis, 0.81 to 0.86 for inflammation, and 0.82 to 0.85 for neoplasm. Radiologists were excellent at recognizing GPA (BA = 0.98 to 0.99) and very good for TED (BA = 0.80 to 0.86). They also did well identifying IgG4-RD (BA = 0.75 to 0.77), but slightly less well for NSOI (BA = 0.69 to 0.75) and poorly for Sarcoid (BA = 0.48 to 0.50). CONCLUSIONS: CT or MRI scanning contributes to the evaluation of patients with orbital disease, but accuracy does varies based depending on the diagnosis. We could not evaluate issues such as determination of disease activity, variability based on the unit used for imaging or the skills beyond those of our two specialized neuroradiologists. Future studies should directly compare the two imaging modalities and assess the utility of imaging to determine disease activity.

The Utility of Preoperative Phenylephrine Testing in Müller Muscle Conjunctival Resection Surgery for Involutional Ptosis.

PURPOSE: Phenylephrine testing prior to Müller muscle conjunctival resection has traditionally been used to predict postoperative outcomes. The purpose of this study is to determine if preoperative phenylephrine testing impacts postoperative changes in eyelid position. METHODS: In this multicenter cross-sectional cohort study, 270 eyelids of participants with involutional ptosis and levator function >12 mm who underwent Müller muscle conjunctival resection were divided into 2 comparison groups. Participants who had preoperative phenylephrine testing served as the control group and those who did not were the study group. The primary outcome measure was postoperative marginal reflex distance from the upper eyelid margin (marginal reflex distance 1 [MRD1]) at the latest follow-up visit. Secondary outcomes included change in MRD1, reoperation rate, and predictive capacity of preoperative phenylephrine testing. RESULTS: Of the 270 eyelids that underwent Müller muscle conjunctival resection, 116 eyelids served as controls and 154 were in the study group. Mean age of participants was 62.6 years. Levator function, resection length, preoperative MRD1, change in MRD1, and latest postoperative MRD1 measures when compared in the control and study groups demonstrated no significance (p > 0.05) via 2-tailed t-test. Postoperative MRD1 was correctly predicted within 1 mm for 60.2% of eyelids that underwent preoperative phenylephrine testing. CONCLUSIONS: Preoperative phenylephrine testing does not significantly predict postoperative eyelid elevation following Müller muscle conjunctival resection. Surgeons may thereby reassess the utility of preoperative phenylephrine testing given the lack of influence on surgical outcomes.

Orbital decompression following treatment with teprotumumab for thyroid eye disease.

OBJECTIVE: To quantify the observed decrease in orbital decompressions being performed at one tertiary care institution and to determine the rate and predictive factors of orbital decompression surgery following treatment with teprotumumab for thyroid eye disease. METHODS: Epic's SlicerDicer program was used to analyze recent trends in the overall number of thyroid eye disease (TED) patients evaluated in the oculoplastic surgery department, as well as usage trends of CPT codes 67445 (lateral orbitotomy with bone removal for decompression) and 67414 (orbitotomy with removal of bone for decompression). A retrospective chart review of active moderate-to-severe TED patients treated with teprotumumab was performed at a single tertiary care center. The main outcome measure was whether or not patients underwent bony orbital decompression surgery following treatment with teprotumumab. The SlicerDicer search demonstrated stable usage of CPT codes 67445 and 67414 from 2016 to 2019, followed by a significant decrease from 2020 to 2023, over a background of increasing numbers of TED patients evaluated in clinic. Following teprotumumab therapy, 25% of patients and 18% of orbits underwent bony decompression. Surgically decompressed patients had higher pre- and post-teprotumumab exophthalmometry measurements compared with patients who did not undergo bony decompression. Average time to decompression following conclusion or cessation of teprotumumab therapy was 12.6 months. CONCLUSION: While the number of TED patients treated at one tertiary care center has risen over recent years, the number of orbital decompression surgeries has declined. Orbital decompression, however, is still needed in select patients after treatment with teprotumumab.

Outcomes of centrally versus laterally based tarsoconjuctival pedicle flap reconstruction for large full thickness lower eyelid defects.

BACKGROUND: To compare the outcomes of two types of tarsoconjunctival pedicle flaps for reconstruction of large lower eyelid defects. METHODS: Retrospective medical record review of consecutive patients who underwent centrally-based or laterally-based tarsoconjunctival pedicle transconjunctival flap for lower eyelid reconstruction for defects greater than 50% of the lid margin. Full thickness skin grafts were used for anterior lamellar reconstruction in all cases. The primary outcome measure was eyelid position, function and satisfactory cosmesis. RESULTS: Forty-three patients were identified. Twenty-six patients underwent reconstruction with a centrally-based tarsoconjunctival pedicle flap; 17 patients underwent reconstruction with a laterally-based tarsoconjunctival pedicle flap. The average size of the lid defect was 77.7% (range 50-100%) in the central group and 75% (range 50-100%) in the lateral group (p=0.604). Mean follow up time was 61.5 weeks in the central group and 46.6 weeks in the lateral group (p=0.765). After division of the flap and during follow up, 27% of the centrally based group required revisional surgery with none in the laterally based group (p=0.03). 100% of the patients with centrally based flaps required second staged division of flap, whereas only 52% of patients with a laterally based flaps underwent second staged flap division. (p<0.001). CONCLUSION: Outcome suggests that for reconstruction of large lower lid defects requiring lid sharing procedures, both centrally and lateral-based procedures have equivalent functional outcome. However, the laterally based group has less need for revisional procedures and may not need a second stage division of the flap.

Effects of Teprotumumab on Eyelid Retraction in Thyroid Eye Disease.

PURPOSE: This study evaluates the efficacy of teprotumumab in reducing eyelid retraction in thyroid eye disease (TED) patients. METHODS: This retrospective study included patients with active or chronic moderate-to-severe TED who completed at least 4 cycles of teprotumumab. Patients with upper and/or lower eyelid retraction, defined as margin-to-reflex distance (MRD) 1 and/or MRD2 of more than 5 mm, in one or OU were included. The main outcome measure was a change in MRD1 and MRD2 after treatment. Changes in MRD1 and MRD2 were each analyzed for correlation (r) with changes in exophthalmolmetry. Student t test was performed for each comparison, and p values <0.05 were considered significant. RESULTS: The study included 91 patients, predominantly female (87%), with an average age of 52.02 ± 14.6 years. The mean baseline proptosis measurement was 21.8 ± 2.9 OD and 21.7 ± 3.3 OS. The average MRD1 was 5.5 ± 1.5 OD and 5.4 ± 1.7 OS, and the average MRD2 was 6.1 ± 1.1 OD and 6.2 ± 1.1 OS. The follow-up duration post-treatment was 37.5 ± 31.7 weeks. At first follow-up post-treatment, the mean change in proptosis, MRD1, and MRD2 were -2.6 ± 2.0 OD, -2.5 ± 2.1 OS, -0.8.5 ± 1.4 OD, -0.8 ± 1.0 OS, and -0.7 ± 0.9 OD, -0.8 ± 1.0 OS, respectively. Correlation analysis showed that proptosis reduction was positively correlated with MRD1 and MRD2 reduction at the first post-treatment follow-up (MRD1: r = 0.23, p value < 0.01; MRD2: r = 0.17, p = 0.03]. CONCLUSION: Teprotumumab treatment improves upper and lower eyelid retraction. The improvement in MRD correlated positively with proptosis reduction, indicating the influence of globe position on eyelid position.

Is Blepharoplasty Cost-effective? Utility Analysis of Dermatochalasis and Cost-effectiveness Analysis of Upper Eyelid Blepharoplasty.

PURPOSE: This cross-sectional prospective study measured utility values of upper eyelid dermatochalasis to quantify its impact on quality of life and assess cost-effectiveness of upper blepharoplasty. METHODS: Utility of dermatochalasis was assessed using the standard reference gamble and time trade-off methods, with dual anchor points of perfect eye function and perfect health. The utility value obtained was used to create a Markov model and run a cost-effectiveness analysis of blepharoplasty as a treatment for dermatochalasis while utilizing the societal perspective. RESULTS: One hundred three patients with dermatochalasis recruited from an urban outpatient ophthalmology clinic completed the utility survey. The authors determined utility values for dermatochalasis ranging from 0.74 to 0.92 depending on the measurement method (standard reference gamble/time trade-off) and anchor points. The cost-effectiveness analysis yielded an incremental cost-effectiveness ratio of $3,146 per quality-adjusted life year, well under the conventional willingness-to-pay threshold of $50,000 per quality-adjusted life year. Probabilistic sensitivity analysis with Monte Carlo simulation demonstrated that blepharoplasty would be cost-effective in 88.1% of cases at this willingness-to-pay threshold. CONCLUSIONS: Dermatochalasis has an impact on quality of life that is significantly associated with level of perceived functional impairment. Rising health care costs have underscored the importance of providing value-based treatment to patients, and the results of this study suggest that blepharoplasty is a cost-effective treatment option for symptomatic bilateral upper eyelid dermatochalasis.

Reconstruction of Full-Thickness Eyelid Defects Following Tumor Resection: The Bucket Handle Modification.

PURPOSE: To describe a modified approach for full-thickness lower eyelid defect reconstruction. METHODS: This is a retrospective review of 5 patients with large full-thickness lower eyelid defects after tumor resection requiring reconstruction. For these lower eyelid defects, a lateral-based or superior-based tarsoconjunctival pedicle flap from the upper eyelid was used to rebuild the posterior lamella. In all cases, the anterior lamella was supplied from an adjacent myocutaneous flap in a bucket handle configuration. Data collection included tumor type and location, size of eyelid defect, presence of canalicular involvement, postoperative eyelid position, patient satisfaction, and complication rates. RESULTS: Five eyelids of 5 patients underwent Mohs micrographic excision of basal cell carcinoma followed by reconstruction with a bucket handle flap. Age range was 68 to 96 years old (mean of 81 y). Five patients presented with lower eyelid involvement. The defect size ranged from 80% to 100% of the eyelid. Three patients had canalicular involvement and required bicanalicular nasolacrimal stent placement. After reconstruction, all patients showed good eyelid apposition to the globe with excellent esthetic outcome. No revision procedures were done. Average follow-up time was 13 months (range of 8 to 21 mo). CONCLUSION: The bucket handle flap for full-thickness eyelid reconstruction is a simple technique that allows for preservation of all anatomical layers of the anterior lamella. This technique shows promising functional and esthetic outcomes.

Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation ( p < 0.001), without significant change in mean horizontal deviation ( p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye ( p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Evaluating the Accuracy of ChatGPT and Google BARD in Fielding Oculoplastic Patient Queries: A Comparative Study on Artificial versus Human Intelligence.

PURPOSE: This study evaluates and compares the accuracy of responses from 2 artificial intelligence platforms to patients' oculoplastics-related questions. METHODS: Questions directed toward oculoplastic surgeons were collected, rephrased, and input independently into ChatGPT-3.5 and BARD chatbots, using the prompt: "As an oculoplastic surgeon, how can I respond to my patient's question?." Responses were independently evaluated by 4 experienced oculoplastic specialists as comprehensive, correct but inadequate, mixed correct and incorrect/outdated data, and completely incorrect. Additionally, the empathy level, length, and automated readability index of the responses were assessed. RESULTS: A total of 112 patient questions underwent evaluation. The rates of comprehensive, correct but inadequate, mixed, and completely incorrect answers for ChatGPT were 71.4%, 12.9%, 10.5%, and 5.1%, respectively, compared with 53.1%, 18.3%, 18.1%, and 10.5%, respectively, for BARD. ChatGPT showed more empathy (48.9%) than BARD (13.2%). All graders found that ChatGPT outperformed BARD in question categories of postoperative healing, medical eye conditions, and medications. Categorizing questions by anatomy, ChatGPT excelled in answering lacrimal questions (83.8%), while BARD performed best in the eyelid group (60.4%). ChatGPT's answers were longer and potentially more challenging to comprehend than BARD's. CONCLUSION: This study emphasizes the promising role of artificial intelligence-powered chatbots in oculoplastic patient education and support. With continued development, these chatbots may potentially assist physicians and offer patients accurate information, ultimately contributing to improved patient care while alleviating surgeon burnout. However, it is crucial to highlight that artificial intelligence may be good at answering questions, but physician oversight remains essential to ensure the highest standard of care and address complex medical cases.

The influence of orbital architecture on strabismus in craniosynostosis.

PURPOSE: To better characterize the correlation of bony orbital dysmorphology with strabismus in craniosynostosis. METHODS: The medical records of patients with craniosynostosis with and without strabismus seen at Rady Children's Hospital (San Diego, CA) from March 2020 to January 2022 were reviewed retrospectively in this masked, case-control study. Computed tomography scans of the orbits were analyzed to obtain dimensions of the orbital entrance and orbital cone. Primary outcome was correlation of strabismus with orbital measurements. RESULTS: A total of 30 orbits from 15 patients with strabismus and 15 controls were included. Craniofacial disorders included in the study were nonsyndromic craniosynostosis (63%), Crouzon syndrome (13%), Apert syndrome (13%), and Pfeiffer syndrome (10%). Orbital index (height:width ratio) (P = 0.01) and medial orbital wall angle (P = 0.04) were found to differ significantly between the strabismus and control groups. CONCLUSIONS: In our small cohort, bony orbital dimensions, including the ratio of orbital height to width and bowing of the medial orbital wall, were associated with strabismus in craniosynostosis.

Preoperative Risk Factors for Proptosis Recurrence After Rehabilitative Orbital Decompression in Graves' Orbitopathy Patients.

PURPOSE: Rehabilitative orbital decompression treats disfiguring exophthalmos in patients with Graves' orbitopathy (GO). This study aimed to identify risk factors associated with the postoperative recurrence of proptosis after orbital decompression. DESIGN: Retrospective, case-control study. METHODS: This retrospective review included patients with GO who underwent rehabilitative orbital decompression for disfiguring proptosis in an inactive state with a low clinical activity score (0-2) between January 2017 and December 2020 by a single surgeon. Exophthalmos was measured using a Hertel exophthalmometer, and recurrence was defined as an increase of 2 mm or more after decompression during the follow-up period. The association between preoperative variables and proptosis recurrence was analyzed using multivariable logistic regression. RESULTS: Of the total 217 patients, 11 (5.1%) developed recurrence of proptosis during the follow-up period (range, 3-30; mean, 15.6 months). Univariate logistic regression analysis identified thyroid-stimulating hormone receptor antibody (TRAb) and thyroid-stimulating immunoglobulin (TSI) as significant factors for recurrence, with age, sex, smoking, disease duration, orbital radiotherapy, and total thyroidectomy history being nonsignificant. TRAb remained significant in a multivariate logistic regression analysis (odds ratio, 1.06; P = .014). Receiver operating characteristic curve analysis revealed an area under the curve of 0.86 with a sensitivity of 90.9% and specificity of 82.0% at a TRAb level of 7.96 IU/L. CONCLUSION: Preoperative TRAb and TSI are valuable markers to predict proptosis recurrence after orbital decompression. These results may help surgeons to decide the optimal timing for orbital decompression to lessen the risk of postoperative recurrence of proptosis.

A comparison of proptosis reduction with teprotumumab versus surgical decompression based on fat-to-muscle ratio in thyroid eye disease.

PURPOSE: To explore if orbital fat-to-muscle ratio (FMR) is predictive of whether surgical decompression or teprotumumab leads to greater proptosis reduction in thyroid eye disease (TED). METHODS: A single-center retrospective cohort study comparing surgical decompression with teprotumumab according to FMR. All TED patients completing an 8-dose course of teprotumumab between January 2020 and September 2022 and all patients undergoing bony orbital decompression from January 2017 to December 2019 were included. Subjects were excluded if they were <18 years, received both surgical decompression and teprotumumab, or lacked orbital imaging. The primary exposure variable was teprotumumab or surgical decompression. The secondary exposure variable was baseline FMR. The primary outcome measure was change in proptosis (mm). RESULTS: Thirty-eight patients, mean age 53.5 years (±11.4), were included in the teprotumumab group and 160 patients, mean age 48 years (±11.1), in the surgical group. Average proptosis reduction after teprotumumab and surgical decompression was 3 mm (±1.44) and 5 mm (±1.75), respectively. The FMR was stratified at the median of 1.80. In subjects with FMR < 1.80, teprotumumab showed equivalent proptosis reduction compared to surgical decompression, -0.33 mm (SE 1.32) p = .802. In subjects with FMR ≥ 1.80, surgical decompression led to significantly more proptosis reduction than teprotumumab, 3.01 mm (SE 0.54), p < .001. CONCLUSIONS: Baseline FMR can be used to counsel patients as to proptosis reduction with teprotumumab versus surgery. Subjects with low FMR obtain comparable proptosis reduction with teprotumumab or surgery, whereas high FMR is associated with more significant proptosis reduction following surgery over teprotumumab.

Transcutaneous retrobulbar amphotericin B for rhino-orbital-cerebral mucormycosis: a multi-center retrospective comparative study.

PURPOSE: To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM). METHODS: In this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality. RESULTS: Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality. CONCLUSIONS: Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

Phospholipase C-γ as a Potential Therapeutic Target for Graves' Orbitopathy.

BACKGRUOUND: Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves' orbitopathy (GO). METHODS: The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1ß to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting. RESULTS: PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P<0.05). PLCG1 and PLCG2 mRNA expression was significantly increased (P<0.05) in IL-1ß, tumor necrosis factor-α, and a cluster of differentiation 40 ligand-stimulated GO fibroblasts. U73122 significantly inhibited the IL-1ß-induced expression of proinflammatory molecules, including IL-6, IL-8, monocyte chemoattractant protein-1, cyclooxygenase-2, and intercellular adhesion molecule-1 (ICAM-1), and phosphorylated protein kinase B (p-Akt) and p38 (p-p38) kinase in GO fibroblasts, whereas it inhibited IL-6, IL-8, and ICAM-1, and p-Akt and c-Jun N-terminal kinase (p-JNK) in normal fibroblasts (P<0.05). CONCLUSION: PLC-γ-inhibiting U73122 suppressed the production of proinflammatory cytokines and the phosphorylation of Akt and p38 kinase in GO fibroblasts. This study indicates the implications of PLC-γ in GO pathogenesis and its potential as a therapeutic target for GO.

Teprotumumab-related Cutaneous Hypersensitivity Reactions.

The authors report 4 cases of cutaneous hypersensitivity reactions developing in the course of teprotumumab treatment for thyroid eye disease. The onset of the cutaneous hypersensitivity reaction was also observed during the treatment course in all cases, between the second and fifth infusions. Teprotumumab-related cutaneous reactions suggest a possible immunogenic component of the monoclonal antibody and highlight the importance of close monitoring during treatment.

The Role of Adipsin, Complement Factor D, in the Pathogenesis of Graves' Orbitopathy.

Purpose: Graves' orbitopathy (GO) is an orbital manifestation of autoimmune Graves' disease, and orbital fibroblast is considered a target cell, producing pro-inflammatory cytokines and/or differentiating into adipocytes. Adipose tissue has been focused on as an endocrine and inflammatory organ secreting adipokines. We investigated the pathogenic role of a specific adipokine, adipsin, known as complement factor D in Graves' orbital fibroblasts. Methods: The messenger RNA (mRNA) expression of multiple adipokines was investigated in adipose tissues harvested from GO and healthy subjects. Adipsin protein production was analyzed in primary cultured orbital fibroblasts under insulin growth factor (IGF)-1, CD40 ligand (CD40L) stimulation, and adipogenesis. The effect of blocking adipsin with small interfering RNA (siRNA) on pro-inflammatory cytokine production and adipogenesis was evaluated using quantitative real-time PCR, Western blot, and ELISA. Adipogenic differentiation was identified using Oil Red O staining. Results: Adipsin gene expression was significantly elevated in GO tissue and increased after the stimulation of IGF-1 and CD40L, as well as adipocyte differentiation in GO cells. Silencing of adipsin suppressed IGF-1-induced IL-6, IL-8, COX2, ICAM-1, CCL2 gene expression, and IL-6 protein secretion. Adipsin suppression also attenuated adipocyte differentiation. Exogenous treatment of recombinant adipsin resulted in the activation of the Akt, ERK, p-38, and JNK signaling pathways. Conclusions: Adipsin, secreted by orbital fibroblasts, may play a distinct role in the pathogenesis of GO. Inhibition of adipsin ameliorated the production of pro-inflammatory cytokines and adipogenesis in orbital fibroblasts. Our study provides an in vitro basis suggesting adipsin as a potential therapeutic target for GO treatment.