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.

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.

Sarcopenia as a potential risk factor for senile blepharoptosis: Nationwide Surveys (KNHANES 2008-2011).

As the world's population is aging, sarcopenia is recognized as essential to assess people's lifelong condition and do appropriate early intervention. Senile blepharoptosis is also a problem in old age deteriorating visual function and causing a cosmetic decline. We investigated the association between sarcopenia and the prevalence of senile blepharoptosis, using a nationwide representative survey in Korea. A total of 11,533 participants were recruited. We used the body mass index (BMI)- adjusted appendicular skeletal muscle (ASM) definition as the muscle mass index (MMI, ASM [kg] divided by BMI [kg/m2]). The association between blepharoptosis prevalence and MMI was analyzed using multivariate logistic regression. Sarcopenia, defined as the lowest MMI quintile group in both men and women, was also associated with the prevalence of blepharoptosis (ORs 1.92, 95% CI 1.17-2.16; p < 0.001). These associations remained statistically significant after adjusting for various factors related to blepharoptosis using multivariate analysis (ORs 1.18, 95% CI 1.04-1.34; p = 0.012). Moreover, MMI was found to have a proportional relationship with eyelid lifting force (levator function), which is closely related to the occurrence and severity of ptosis. Sarcopenia is related to the prevalence of senile blepharoptosis, and patients with lower MMI were more likely to have blepharoptosis. These results suggest that sarcopenia can affect visual function and aesthetics.

Therapeutic effect of modified double-dose photodynamic therapy in circumscribed choroidal haemangioma.

AIMS: To retrospectively compare the therapeutic effect of modified double-dose photodynamic therapy (PDT) with standard-dose PDT in patients with circumscribed choroidal haemangioma (CCH). METHODS: Thirty-nine patients with CCH were categorised in two groups by PDT type. The standard-dose group (n=12) was treated with 6 mg/m2 verteporfin and a 689 nm laser for 83 s. The modified double-dose group (n=27) received one vial of verteporfin (15 mg), and the dose was calculated for each patient based on body surface area, then irradiance time was adjusted according to calculated verteporfin dose to achieve a 'double'-dose effect. Treatment outcomes (foveal centre thickness, subretinal fluid, tumour thickness and diameter) were measured at baseline and 1 year post-treatment; subretinal fluid levels were also measured at 1, 3 and 6 months post-treatment. RESULTS: No differences in baseline characteristics were found between the two groups. The modified double-dose group showed a greater reduction in tumour thickness (45.3% vs 20.6%, p=0.013) and tumour volume (60.0% vs 30.0%, p=0.006) at 1 year post-treatment. Recurred or non-complete resolution patients in the standard-dose group tended to show much increased subretinal fluid than those in the modified double-dose group at 1-year post-treatment. CONCLUSION: Modified double-dose PDT is an effective and safe protocol for symptomatic CCH management, greater tumour regression and potentially better resolution of subretinal fluid compared with standard PDT.

Protein tyrosine phosphatase 1B as a therapeutic target for Graves' orbitopathy in an in vitro model.

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1ß, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-ß stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1ß, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1ß-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-ß-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.

Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.

BACKGROUND/AIMS: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. METHODS: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson's trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). RESULTS: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFß in vitro. CONCLUSIONS: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.

Delta neutrophil index (DNI) as a novel diagnostic and prognostic marker of infection: a systematic review and meta-analysis.

OBJECTIVE: Delta neutrophil index (DNI) representing the number of immature granulocytes is an emerging marker used in diagnosis of infections and prediction of mortality in infected patients. The present study evaluated the diagnostic accuracy of DNI as a predictive and prognostic factor in infected patients. METHODS: We performed a PubMed search on January 1st, 2017 and identified studies that evaluated DNI as either a predictive or prognostic factor in infected patients. Studies with appropriate information to construct 2 × 2 contingency tables were extracted. We calculated pooled sensitivity and specificity. Meta-analysis of the multivariate logistic regression data set was performed to assess whether DNI functions as an independent factor. RESULTS: Overall, 12 articles fulfilled the inclusion criteria and a total of 499 cases and 9549 controls were examined. As a predictive factor of infection, DNI's pooled sensitivity was 0.67 (95% CI 0.62-0.71, I 2 = 86.0%) and pooled specificity was 0.94 (95% CI 0.94-0.95, I 2 = 92.8%). Area under the receiver operating characteristics (ROC) curve was 0.89. As a prognostic factor for death in infected patients, DNI's pooled sensitivity was 0.70 (95% CI 0.56-0.81, I 2 = 0.0%) and pooled specificity was 0.78 (95% CI 0.73-0.83, I 2 = 26.6%). Area under the ROC curve was 0.84. Meta-analysis of the multivariate logistic regression data set showed insignificant results. CONCLUSIONS: DNI is a potentially useful diagnostic tool and predicts mortality among infected patients and should be more widely used in the clinical practice.