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Graves' orbitopathy (GO) is a disfiguring and sight-threatening autoimmune disease. Previous studies have shown the infiltration of macrophages in GO orbital connective tissues. However, the immunophenotypes of macrophages and their modulatory effects on orbital fibroblasts (OF) have not been examined so far. In this study, we sought to determine the pathophysiology of macrophages in GO.In this case-control study, orbital connective tissues collected from 40 GO patients and 20 healthy controls were immunohistochemically stained for cytokines and macrophage cell surface antigens. The polarization of orbital-infiltrating macrophages was investigated by flow cytometry and immunofluorescence. Effects of interleukin (IL)-6 combined with soluble IL-6 receptor (sIL-6R) on the proliferation, differentiation, and inflammation of different OF subsets were examined by CCK-8, Western blotting, and Luminex assays, respectively. The antigen-presenting abilities of different OF subsets under IL-6/sIL-6R signaling were studied by proteomics. Finally, the differentiation of CD8+ IL-17A-producing T cells by sIL-6R was tested.GO orbital connective tissues displayed increased IL-6, sIL-6R, STAT3, and IL-17A levels. CD86+ M1-like macrophages were predominant in active GO patients whilst stable GO patients tended to have more CD163+ M2-like macrophages. The expression of IL-6 was higher in M1-like macrophages and the expression of transforming growth factor-β was higher in M2-like macrophages both in GO orbital connective tissues in situ in vivo and in cell culture system in vitro. The IL-6/sIL-6R stimulation promoted the fibrosis of both CD34+ and CD34- OFs. Monocyte chemoattractant protein-1 expression was also induced by IL-6/sIL-6R stimulation in both OF subsets. IL-6/sIL-6R stimulation enhanced antigen processing of CD34+ OFs via up-regulating the intact major histocompatibility complex I and antigen transporters. However, the protein expressions of thyroid-stimulating hormone receptor and insulin-like growth factor 1 receptor could not be directly increased by IL-6/sIL-6R stimulation in CD34+ OFs. Furthermore, sIL-6R was conducive to the differentiation of CD8+ IL-17A-producing T cells.Our study demonstrated the immunophenotypes of orbital-infiltrating macrophages that may activate OFs depending on the IL-6/sIL-6R signaling in GO. Our preclinical findings implicate, at least in part, the molecular rationale for blocking sIL-6R as a promising therapeutic agent for GO.

Background and aims Obesity, especially abdominal obesity, has been considered a risk factor for diabetic complications. Many abdominal obesity indices have been established, including neck circumference (NC), waist-to-hip ratio (WHR), lipid accumulation product (LAP), visceral adiposity index (VAI) and the Chinese visceral adiposity index (CVAI). However, studies investigating the associations between these indices and diabetic complications are limited. The objective of this study was to investigate the associations of the abdominal obesity indices with cardiovascular and cerebrovascular disease (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR). Methods A total of 4658 diabetic participants were enrolled from seven communities in Shanghai, China, in 2018. Participants completed questionnaires and underwent blood pressure, glucose, lipid profile, and urine albumin/creatinine ratio measurements; fundus photographs; and anthropometric parameters, including height, weight, waist circumference (WC), NC and hip circumference (HC). Results In men, a one standard deviation (SD) increase in CVAI level was significantly associated with a greater prevalence of CVD (OR 1.35; 95% CI 1.13, 1.62) and DKD (OR 1.38; 95% CI 1.12, 1.70) (both P P Conclusions CVAI was most strongly associated with the prevalence of CVD and DKD among the abdominal obesity indices, and NC was unique associated with the prevalence of CCA plaque in Chinese adults with diabetes. Trial registration ChiCTR1800017573, www.chictr.org.cn. Registered 04 August 2018.

Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

Thyroid-associated ophthalmopathy (TAO) is the most common extrathyroidal manifestation of toxic diffuse goiter (Graves' disease), also known as Graves' ophthalmopathy/orbitopathy. As an organ-specific autoimmune disease, the pathogenesis of TAO is still unclear. In recent years, great progress has been made in revealing the mechanism of TAO. Various biological and immunosuppressive agents have emerged in an endless stream, showing encouraging results. Strengthening the basic research, establishing ideal animal models, deeply understanding the pathogenesis, and developing novel targeted drugs are of great significance to guide the clinical diagnosis and management of TAO and improve the prognosis of patients.

To evaluate the age-related difference in EOMs and its relation to clinical manifestations by computed tomography (CT) measurement of EOMs. The medical records and CT image review of 40 patients (80 orbits) with moderate-to-severe Graves’ orbitopathy were performed. The patients were divided into two age groups, group 1 (≤ 40 years) and group 2 (> 40 years). CT scans of 30 gender- and age-matched normal controls were also obtained. The maximal cross-sectional area (MCA) and its position (pMCA) of each EOM were measured. Group 1 presented with more severe proptosis (p

Objective: The objective of this cross-sectional study was to investigate the association of serum 25-hydroxyvitamin D (25[OH]D) levels with estimated glomerular filtration rate (eGFR), al...

Thyroid-associated ophthalmoapthy (TAO) is the most common orbital disease. As an autoimmune disorder, it is caused by self-reactive lymphocytes that escape immune tolerance, but the mechanism is not fully understood. The basic process of TAO is the infiltration of immune cells in orbital tissues, the activation of orbital fibroblasts (OFs), and the proliferation and differentiation of OFs and lymphocytes. Activated OFs secrete inflammatory regulators, growth factors, and chemokines, thereby maintaining and amplifying the immune responses. The interactions between OFs and lymphocytes lead to the expansion and the remodeling of the orbital tissues, presenting the clinical manifestations of TAO. This review will focus on the role of T cell subsets (Type 1, Type 2, Type 17 helper T cells, and regulatory T cells) in the pathogenesis of TAO. However, we still need further studies to unravel the pathogenesis, to confirm current hypotheses, and to provide novel ideas for appropriate clinical treatment of TAO.

Context Unique features of local immunity in thyroid-associated ophthalmopathy (TAO) may affect disease progression. Objective To investigate the association between the orbital immune microenvironment and TAO development. Design/setting/participants TAO and control orbital connective tissues were collected. Main outcome measures Single-cell sequencing examined orbital lymphocytic infiltrates. Multicolor flow cytometry explored the phenotypes of different cell subsets and in vitro models for cell functional studies. Coculture experiment and western blotting assay were used to determine underlying mechanism of the enhanced T helper 17 (Th17) cell pathway. Results The TAO orbital microenvironment was composed of natural killer cells, dendritic cells, macrophages, T cells, plasma cells, and CD34+ orbital fibroblasts, but few B cells. Increases in CD3+CD8- IL-17A-producing and RAR-related orphan receptor (ROR)γt-expressing T cells and in CD3+CD8- IL-13-producing and GATA3-expressing T cells suggested Th17 and Th2 cell responses in TAO orbits. Increased interferon-γ (IFN-γ)-producing and RORγt+Tbet+ T cells indicated a Th1-like phenotype of orbital-infiltrating Th17 cells. Higher IL-23R and IL-1R expression and lower IL-21R expression were also observed on Th17 cells in TAO orbits. Multivariate analyses revealed that the Th17 pathway [IL-17A (P = 0.001), IFN-γ (P = 0.009), RORγt (P = 0.003), IL-23R (P = 0.033), IL-21R (P = 0.019)], and Th2 pathway [IL-13 (P = 0.015), GATA3 (P = 0.012)] were associated with TAO. IL-17A, IL-23R, and IL-1R correlated with clinical activity score and visual acuity. CD34+ orbital fibroblasts exhibited distinct cell surface marker expression and promoted IL-23R and IL-1R expression on T cells to facilitate the Th17-cell phenotype through prostaglandin E2-EP2/EP4-cAMP signaling. Conclusion Our study addresses the importance of retroorbital immunity and suggests possible means of disrupting TAO pathogenesis.

The CD4(+)CD25(+)FOXP3(+) regulatory T (Treg) cells are critical for maintaining immune tolerance in healthy individuals and are reported to restrict anti-inflammatory responses and thereby promote tumor progression, suggesting them as a target in the development of antitumor immunotherapy. Forkhead box P3 (FOXP3) is a key transcription factor governing Treg lineage differentiation and their immune-suppressive function. Here, using Treg cells, as well as HEK-293T and Jurkat T cells, we report that the stability of FOXP3 is directly and positively regulated by the E3 ubiquitin ligase ring finger protein 31 (RNF31), which catalyzes the conjugation of atypical ubiquitin chains to the FOXP3 protein. We observed that shRNA-mediated RNF31 knockdown in human Treg cells decreases FOXP3 protein levels and increases levels of interferon-γ, resulting in a Th1 helper cell–like phenotype. Human Treg cells that ectopically expressed RNF31 displayed stronger immune-suppressive capacity, suggesting that RNF31 positively regulates both FOXP3 stability and Treg cell function. Moreover, we found that RNF31 is up-regulated in Treg cells that infiltrate human gastric tumor tissues compared with their counterparts residing in peripheral and normal tissue. We also found that elevated RNF31 expression in intratumoral Treg cells is associated with poor survival of gastric cancer patients, suggesting that RNF31 supports the immune-suppressive functions of Treg cells. Our results suggest that RNF31 could be a potential therapeutic target in immunity-based interventions against human gastric cancer.

Aims: Some studies have reported associations between bilirubin and diabetic microvascular complications. However, these studies focused only on total bilirubin (TBIL) without distinguishing different bilirubin subtypes. In this study, we aimed to investigate the associations of TBIL, direct bilirubin (DBIL) and indirect bilirubin (IBIL) levels with albuminuria/creatinine ratio (ACR) and the prevalence of diabetic retinopathy (DR) among diabetic adults. Methods: We analyzed 4368 individuals out of 4813 diabetic participants enrolled from seven communities in 2018 in a cross-sectional study. Participants underwent several checkups, including the measurement of anthropometric parameters, blood pressure, glucose, lipid profile, TBIL, DBIL, IBIL and ACR. DR was detected by high-quality fundus photographs and was remotely read by ophthalmologists. Results: Compared with the first quartile of DBIL, participants in the fourth quartile had a lower prevalence of high ACR (odds ratio (OR) 0.76; 95% confidence interval (CI) 0.59, 0.99) ( p for trend Conclusion: DBIL had a stronger association with high ACR and DR than TBIL or IBIL did in diabetic adults. The effect of DBIL on diabetic complications should be noted and investigated in further studies.

Objective The attraction and influx of monocytes into the retina has been considered a critical step in the development of diabetic retinopathy (DR). However, large population studies about the association between peripheral blood monocyte levels, an inexpensive and easily measurable laboratory index, and DR are limited. Thus, we aimed to investigate the association between peripheral blood monocyte levels and DR. Methods A total of 3223 participants out of 3277 adults with diabetes were enrolled from seven communities in China in this cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, routinely analyzed leukocyte characteristics, glucose, lipid profiles, urine albumin/creatinine ratio and fundus photographs. Results The prevalence of DR among the participants in the highest quartile of peripheral blood monocyte levels significantly decreased by 41% (OR 0.59; 95% CI 0.43, 0.81) compared with the participants in the first quartile (P for trend P for trend > 0.05). Associations between leukocyte, neutrophil and lymphocyte levels and DR were also not found (all P for trend > 0.05). These associations were all fully adjusted for age, sex, education status, duration of diabetes history, current smoking, BMI, HbA1c, dyslipidemia, systolic blood pressure and insulin therapy. Conclusion Decreased peripheral blood monocyte levels were associated with increased odds of DR after adjusting for potential confounders in diabetic adults. However, causation remains to be demonstrated.

Objective To evaluate magnetic resonance imaging parameters, T2 signal intensity ratios (SIRs), and normalized apparent diffusion coefficients (n-ADC) of the extraocular muscles (EOMs) in the identification of different stages of Graves’ ophthalmopathy (GO) and to find out the correlation of T2-SIRs and n-ADC values with disease changes after anti-inflammatory treatment. Methods Altogether, 43 patients (86 orbits) were enrolled and classified into “active” or “inactive” stages by clinical activity score (CAS). Twenty-three (53.5%) patients received anti-inflammatory treatment and underwent a follow-up evaluation. Fifteen age- and gender-matched control participants (30 orbits) were included. T2-SIRs and n-ADC values of EOMs were calculated among GO and healthy controls and were correlated with CAS. Changes in these parameters were also evaluated before and after anti-inflammatory treatment. Results Mean T2-SIRs and n-ADC values were both significantly higher in GO patients than in controls and higher in active GO than in inactive GO. In the inactive stage, n-ADC values of inferior rectus muscles were still higher than those in healthy controls. Both T2-SIRs and n-ADC values decreased after intravenous steroid pulse therapy. The cutoff value of pretreatment n-ADC was 1.780 to detect stages with specificity of 93.7% and sensitivity of 48.3% (P = .035). Conclusion T2-SIRs and n-ADC values are valuable magnetic resonance imaging indicators of the inflammatory activity in GO by detecting involvement of EOMs. They are also ideal tools to monitor the efficacy of anti-inflammatory treatment in patients with active stage GO. n-ADC values, when combined with CAS, can be promising predictive factors in the detection of stages of diseases.

Additional file 2: Table S1. Associations between adiposity phenotype indices and the prevalence of diabetic complications without adjusting for BMI. Table S2. Associations between the quartiles of the abdominal obesity indices and the prevalence of CVD. Table S3. Associations between the quartiles of the abdominal obesity indices and the prevalence of DKD. Table S4. Associations between the quartiles of the abdominal obesity indices and the prevalence of DR.

Supplemental material, sj-pdf-2-tae-10.1177_2042018820937897 for Associations between different bilirubin subtypes and diabetic microvascular complications in middle-aged and elderly individuals by Heng Wan, Hui Zhu, Yuying Wang, Kun Zhang, Yi Chen, Sijie Fang, Fangzhen Xia, Ningjian Wang, Wen Zhang and Yingli Lu in Therapeutic Advances in Endocrinology and Metabolism

Supplemental material, sj-pdf-1-tae-10.1177_2042018820937897 for Associations between different bilirubin subtypes and diabetic microvascular complications in middle-aged and elderly individuals by Heng Wan, Hui Zhu, Yuying Wang, Kun Zhang, Yi Chen, Sijie Fang, Fangzhen Xia, Ningjian Wang, Wen Zhang and Yingli Lu in Therapeutic Advances in Endocrinology and Metabolism

Additional file 1: Table S1. Associations between the monocytes level quartiles and the prevalence of DR among the participants without proliferative DR. Table S2. Associations between the monocytes level quartiles and the prevalence of DR among all the 3266 participants. Table S3. Associations between CRP level and diabetic complications.

Objective. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive and easily measurable laboratory index indicating systemic inflammation, while the application of many other inflammatory markers has been limited in daily clinical practice. However, large population studies about investigating the associations of the NLR level with diabetic complications including cardiovascular and cerebrovascular diseases (CVD), diabetic kidney disease (DKD), and diabetic retinopathy (DR) in the same population were limited. The aim of our study is to evaluate the associations between the NLR level and the prevalence of CVD, DKD, and DR in adults with diabetes simultaneously. Methods. A cross-sectional survey of 4,813 diabetic adults was conducted in seven communities in China. Persons underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, routinely analyzed leukocyte characteristics, glucose, lipid profiles, urine albumin/creatinine ratio, and fundus photographs. Results. Compared with the first quartile of the NLR level, the odds of having CVD was significantly increased by 21% for participants in the highest quartile (OR 1.21; 95% CI 1.00, 1.47) (P for trend<0.05). Similarly, the prevalence of DKD among participants in the highest quartile of the NLR level was significantly increased by 150% (OR 2.50; 95% CI 1.95, 3.19) (P for trend<0.05). However, no association was found between the NLR level and the prevalence of DR (P for trend>0.05). These associations were all fully adjusted. Conclusions. A higher NLR level was associated with an increased prevalence of CVD and DKD, other than DR, in diabetic adults.

Background: The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFNα) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFNα and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear. Methods: The interactions between IFNα, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFNα (20 000 IU per day, s.c.), erlotinib (50 mg kg−1 per day, i.g.) and nimotuzumab (10 mg kg−1 per day, i.p.) was further confirmed in vivo using HNSCC xenografts in nude mice. The upregulation of retinoic-acid inducible gene I (RIG-I) induced by IFNα and EGFR-targeted therapies and its mechanism were detected in vitro and in vivo. Results: IFNα enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFNα and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFNα, erlotinib, and nimotuzumab. Moreover, IFNα transcriptionally induced RIG-I expression in HNSCC cells through STAT1. Conclusions: IFNα enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFNα in HNSCC.

Aim Fasting serum C-peptide is a biomarker of insulin production and insulin resistance, but its association with vascular complications in type 2 diabetes mellitus (T2DM) has never been fully elucidated. This study aimed to investigate whether C-peptide is associated with cardiovascular disease (CVD) and diabetic retinopathy (DR). Methods A total of 4793 diabetes patients were enrolled from seven communities in Shanghai, China, in 2018. CVD was defined as a self-reported combination of previous diagnoses, including coronary heart disease, myocardial infarction and stroke. DR was examined using fundus photographs. Logistic regression analyses were performed, and multiple imputed data were used to obtain stabilized estimates. Results Prevalence of CVD increased with increasing C-peptide levels (Q1, Q2, Q3 and Q4: 33%, 34%, 37% and 44%, respectively; Pfor trend Conclusion C-peptide was positively associated with CVD, but inversely associated with DR progression. The association between C-peptide and CVD could be due to associated metabolic risk factors.

Small non-coding RNAs, which are 20–25 nucleotide ribonucleic acids, have emerged as an important transformation in the biological evolution over almost three decades. microRNAs (miRNAs) and short interfering RNAs (siRNAs) are two significant categories of the small RNAs that exert important effects on bone endocrinology and skeletology. Therefore, clarifying the expression and function of these important molecules in bone endocrine physiology and pathology is of great significance for improving their potential therapeutic value for metabolism-associated bone diseases. In the present review, we highlight the recent advances made in understanding the function and molecular mechanism of these small non-coding RNAs in bone metabolism, especially their potentially therapeutic values in bone-related diseases., Highlights • This review systematically investigated the expression and function of miRNA in bone endocrine physiology and pathology. • Comprehensive summary of recent advances made in understanding the potential therapeutic of miRNA and siRNA both in vivo and in vitro. • This study extensively generalized the delivery systems, clinical status and challenges in small non-coding RNAs-based therapeutics for bone-related disorders, together with suggested corresponding countermeasures.

The objective of this study was to investigate the different associations of the serum urate (SUA) level with cardiovascular and cerebrovascular diseases (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR) in Chinese adults.We analyzed 4767 participants out of 4813 adults with diabetes enrolled from seven communities in a cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, SUA, glucose, lipid profiles, urine albumin/creatinine ratio (ACR) and fundus photographs.Compared with the first SUA tertile, the third tertile increased the prevalence of CVD by 22% (OR 1.22; 95% CI 1.01, 1.46) (P for trend0.05) and increased the prevalence of DKD by 59% (OR 1.59; 95% CI 1.28, 1.97) for KDOQI definition. Compared with the first tertile, the OR (95% CI) of the number of diabetic complications, ranging from 0 to 2, associated with SUA level in ordinal logistic regression was 1.75 (1.44, 2.12) for the third tertile (P for trend0.01). These associations were all fully adjusted. No association was found between the prevalence of DR and the SUA level.A higher SUA level was associated with an increased prevalence of CVD and DKD and a variety of diabetic complications, other than DR, in men and postmenopausal women with T2DM. However, the causation remains to be demonstrated.

BACKGROUND Eyelid retraction is the most common and often the first sign of thyroid eye disease (TED). Upper-eyelid retraction causes both functional and cosmetic problems. In order to correct the position of the upper eyelid, surgery is required. Many procedures have demonstrated good outcomes in mild and moderate cases; however, unpredictable results have been obtained in severe cases. Dryden introduced an upper-eyelid-lengthening procedure, which used scleral grafts, but outcomes were unsatisfactory. A new technique is introduced in this study as a reasonable alternative for TED-related severe upper-eyelid retraction correction. MATERIAL AND METHODS An innovative technique for levator lengthening using bovine acellular dermal matrix as a spacer graft is introduced for severe upper-eyelid retraction secondary to TED. Additionally, 2 modifications were introduced: the fibrous cords scattered on the surface of the levator aponeurosis were excised and the orbital fat pad anterior to the aponeurosis was dissected and sutured into the skin closure in a "skin-tarsus-fat-skin" fashion. RESULTS The modified levator-lengthening surgery was performed on 32 eyelids in 26 patients consisting of 21 women and 5 men (mean age, 37.8 years; age range, 19-67 years). After corrective surgery, the average upper margin reflex distance was lowered from 7.7±0.85 mm to 3.3±0.43 mm. Eighteen cases (69%) had perfect results, while 6 cases (23%) had acceptable results. CONCLUSIONS A modified levator-lengthening procedure using bovine acellular dermal matrix as a spacer graft ameliorated both the symptoms and signs of severe upper-eyelid retraction secondary to TED. This procedure is a reasonable alternative for correction of TED-related severe upper-eyelid retraction.

The aim of this study was to compare the surgical outcomes of deep lateral orbital decompression using the rim-sparing technique versus the rim-removal technique in Graves’ orbitopathy (GO). A retrospective cohort study of 75 orbits in 50 patients with GO was performed. Proptosis, best corrected visual acuity (BCVA), intraocular pressure (IOP), upper and lower lid margin to reflex distances (MRD-1 and MRD-2, respectively), diplopia, ocular restriction, and GO quality of life (GO-QOL) questionnaire results were analyzed pre- and postoperatively. The average proptosis reduction ranged from 3.5 mm to 6.7 mm with the rim-sparing technique and from 3.6 mm to 6.7 mm with the rim-removal technique ( P > 0.05). All orbits with dysthyroid optic neuropathy in the rim-sparing group and 87.5% of such orbits in the rim-removal group showed improved BCVA ( P = 0.321). Reductions in IOP, MRD-1, and MRD-2 were observed with both techniques. Patients in the rim-sparing group had greater improvements in GO-QOL appearance score ( P = 0.043). In conclusion, rim-sparing orbital decompression provides efficacious outcomes with greater improvements in patient quality of life than the rim-removal technique. The rim-sparing technique should be considered as a preferable option because it preserves the integrity of the lateral vertical maxillary buttress and bony protection for the orbital contents.

Background Thyroid eye disease (TED) is a debilitating autoimmune orbital disease that is often a result of Graves’ disease. Dysthyroid optic neuropathy (DON) is a rare but sight-threatening manifestation of TED with therapeutic challenges that can potentially lead to visual loss. Case presentation A 74-year-old man experienced active TED with extremely severe redness and swelling of the conjunctiva, loss of visual acuity and exacerbation of disfiguring proptosis. Computed tomography revealed the involvement of extraocular muscles resulting in optic nerve compression. He was in poor general condition and was intolerant to steroids. To achieve the optimal operating conditions for orbital decompression surgery, the patient was initially treated with orbital radiotherapy. The patient responded well, with improvements in clinical activity score and visual acuity. Conclusion This case demonstrates a rare and severe case of DON with therapeutic challenges. To date, no cases has been reported of a patient with such severe and unusual ocular manifestations. Early awareness of the occurrence of optic nerve compression and prompt treatment are important to prevent irreversible outcomes. Orbital radiotherapy should be considered as a useful surgery-delaying alternative for DON, especially in patients who have contraindications to steroids.

MicroRNAs (miRNAs) are endogenous small noncoding ~22-nt RNAs, which have been reported to play a crucial role in maintaining bone development and metabolism. Osteogenesis originates from mesenchymal stem cells (MSCs) differentiating into mature osteoblasts and each period of bone formation is inseparable from the delicate regulation of various miRNAs. Of note, apprehending the sophisticated circuit between miRNAs and osteogenic homeostasis is of great value for artificial skeletal regeneration for severe bone defects. In this review, we highlight how different miRNAs interact with diverse osteo-related genes and endeavor to sketch the contours of potential manipulations of miRNA-modulated bone repair.

Background Intravenous glucocorticoids (ivGC) have been recommended as a first-line treatment of moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). However, not all patients are responsive to ivGC. The identification of potential factors used to predict their efficacy and the selection of suitable patients have both been lacking. Methods It was a single center retrospective study. Potential factors related to the effects of ivGC were analyzed using logistic regression in 90 consecutive patients with moderate-to-severe and active TAO, who received 4.5 g ivGC therapy. Response was defined as the achievement of at least three points of the overall response. Results Fifty-two (57.8%) patients showed a positive response to ivGC therapy. Significant correlations were observed between the effects of ivGC and pretreatment clinical activity score (CAS), duration of eye symptoms, and restoration of euthyroidism. The two latter factors were both independent. The duration of eye symptoms was negatively correlated with the effects of ivGC, with an odds ratio (OR) of 0.984 (p = 0.012). Restoration of euthyroidism (OR = 3.282, p = 0.039) and pretreatment CAS (OR = 1.653, p

Context T helper (Th)17 cells are correlated with many human autoimmune disorders, including Graves disease, and may play key roles in the pathogenesis of Graves orbitopathy (GO). Objective To study the phenotype of Th17 cells in patients with GO and healthy subjects, investigate the fibrosis and adipogenesis in orbital fibroblasts (OFs) modulated by interleukin (IL)-17A, and determine the interaction between Th17 cells and OFs. Design/Setting/Participants Blood samples and orbital tissues from GO patients and healthy controls were collected. Main Outcome Measures We conducted multicolor flow cytometry, immunohistochemical and immunofluorescent stainings, Western blotting, a PathScan intracellular signaling assay, Luminex and enzyme-linked immunosorbent assays, and protein mass spectrum. Results Interferon-γ– and IL-22–expressing Th17 cells are increased in GO patients, which are positively related to clinical activity score. Costimulatory molecules are highly expressed in GO orbits and most GO OFs are CD90+. IL-17A promotes TGF-β–induced fibrosis in CD90+ OFs but impedes 15-deoxy-Δ12,14-prostaglandin J2–induced adipogenesis in CD90− OFs. Th17 cells promote proinflammatory cytokine secretion in both CD90+ and CD90− OFs. Meanwhile, both CD90+ and CD90− OFs contribute to Th17 cell differentiation through prostaglandin E2 production, which can be attenuated by indomethacin. Furthermore, Th17 cells upregulate costimulatory molecule expression on OFs. Conclusion Our findings unravel the pathogenicity of IL-17A in the initiation and progression of GO. In-depth interpretation of the molecular basis of OFs delineated by CD90 and Th17–OF interaction will help to afford a novel approach to better therapeutic strategies for GO.

Purpose This present study aims to investigate the phenotype of IL-17A-producing T cells in thyroid-associated ophthalmopathy (TAO) and the role of IL-17A on RANTES and IL-16 expression in orbital fibroblasts (OFs) from TAO patients. Methods Blood samples were obtained from TAO patients and healthy controls and were subjected to ELISA and flow cytometry analysis. Primary human OFs cultured from surgical wastes were stimulated with IL-17A in the presence or absence of CD40L and were examined by qRT-PCR, ELISA, Western blotting, and apoptosis assays. Results We reported upregulated IL-17A, IFN-γ, RANTES, and IL-16 serum levels and increased frequency of IL-17A- and IFN-γ-producing T cells in peripheral blood mononuclear cells from patients with TAO compared with healthy controls. In addition, TAO orbital tissues were rich in T lymphocytes, expressing more IL-17A, IFN-γ, RANTES, and IL-16. Moreover, IL-17A could enhance the expression of RANTES, but not IL-16, in cultured primary OFs in cooperation with CD40L. We further validated that MAPK signaling was largely responsible for RANTES production in IL-17A-treated OFs. Finally, we demonstrated that IL-17A could not promote apparent apoptosis in OFs from TAO patients and healthy controls. Conclusions Our results indicate the potent effect of IL-17A-induced RANTES expression on OFs and elaborate a possible mechanism in understanding Th17 cells in the pathology of TAO and its potential as a target to immunotherapy of TAO and other autoimmune disorders.

Context: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO. Objective: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO. Design/Setting/Participants: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects. Main Outcome Measures: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed. Results: Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4+ and CD8+ T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients. Conclusion: Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.

Purpose Recent reports suggest that Th17 immunity and bone marrow-derived CD34+ fibrocytes contribute to the pathogenesis of Graves' orbitopathy (GO). This study investigated interactions between Th17 cells and fibrocytes in GO inflammation in Chinese subjects. Methods Th17 cells and fibrocytes were derived from blood samples from Chinese GO patients and healthy controls. Proportions and phenotypes of Th17 cells, regulatory T cells (Tregs), and fibrocytes were examined by flow cytometry. Exogenous IL-17A was used to study inflammatory activity of fibrocytes from GO patients and control subjects. Coculture, quantitative RT-PCR, Luminex, and transwell assays were performed to investigate the relationship between Th17 cells and fibrocytes. Results CC-chemokine receptor 6 (CCR6+) Th17 cells were increased in both active (P < 0.001) and inactive (P < 0.05) GO patients, compared with healthy controls. There was a positive correlation between number of CCR6+ Th17 cells and GO clinical activity score (P < 0.0001, r = 0.8176). Further, CD34+ fibrocytes were increased in GO patients, with increased expression of IL-17RA (P < 0.05), CD80 (P < 0.05), and CD86 (P < 0.05). A decreased population of effector Treg cells (P < 0.01) and increased CTLA-4 expression on naive Treg cells (P < 0.05) were observed in GO patients. IL-17A stimulated cytokine production in fibrocytes; GO fibrocytes exhibited more robust production than normal fibrocytes. Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; conversely, fibrocytes enhanced Th17 cell-function and recruited Th17 cells in a macrophage inflammatory protein 3 (MIP-3)/CCR6-dependent manner. Conclusions The crosstalk between CCR6+ Th17 cells and fibrocytes plays a role in the pathogenesis of GO. Suppressing these interactions may be a candidate molecular target for therapeutic approaches of GO.