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Abstract 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.

PurposeTo evaluate the age-related difference in EOMs and its relation to clinical manifestations by computed tomography (CT) measurement of EOMs.MethodsThe 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.ResultsGroup 1 presented with more severe proptosis (p < 0.001), while group 2 had a higher risk of diplopia (p < 0.001). Motility restriction in supraduction was more likely to occur in Group 2 (p = 0.027) with even higher severity (p = 0.047). The pMCA was higher in the inferior (p = 0.001), medial (p = 0.021), and lateral rectus (p = 0.013) in group 1. Proptosis was positively correlated to pMCA while diplopia was correlated to MCA in both groups. Significant correlation was noted between restrictions levels and MCA (superior, r = 0.467, p < 0.001; inferior, r = 0.358, p = 0.007; medial, r = 0.314, p = 0.018; lateral, r = 0.308, p = 0.021) or pMCA (inferior, r =  − 0.534, p < 0.001) only in group 2.ConclusionsThe muscle enlargement patterns are significantly different between younger and older patients. Older patients tended to have enlarged muscle bellies more posterior in the orbit, which is responsible for more diplopia and motility restriction. Proptosis is more likely to be affected by the most enlarged position than muscle size. So younger patients tended to develop more proptosis and be less bothered by motility restriction even with enlarged muscles.

Background: Tumor necrosis factor (TNF)-α can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-α by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF-α-induced PAI-1 upregulation and the underlying mechanisms were evaluated. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. Results: Adp decreased the TNF-α-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-α-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-α-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. Conclusions: Our data suggest that Adp abrogates TNF-α-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases.

Ensuring the harmonization between urbanization and water environment systems is imperative for fostering sustainable regional development in the future. With urban agglomerations and metropolitan areas increasingly dominating urbanization trends in China, it is crucial to explore the interdependent relationship between urbanization and the water environment. Such exploration holds significant implications for water resource management and the formulation of urbanization policies. This study utilizes a comprehensive index system encompassing urbanization and the water environment. It examines the coupled and coordinated spatial and temporal dynamics of these systems within the Chengdu-Chongqing Urban Agglomeration from 2011 to 2019. This analysis employs the Coupled Coordination Degree model alongside the spatial autocorrelation model. The results show that there is still much room for improving the urbanization development level and the water environment quality. During the study period, a nonlinear and nearly U-shaped evolutionary trajectory was observed between the two systems. The results suggest that there is a progression from basic to more advanced coordination between urbanization and water environment at the city cluster scale. Urbanization appears to generally lag behind the water environment in terms of coordination. At the municipal scale, there is a gradient in which some cities show better coordination compared to others. Spatially, the coupling and coordination of this region exhibited dual-core development characteristics centered around Chengdu and Chongqing. The region is in the transition stage towards a core-type networked and decentralized development mode, which has not yet formed an integrated pattern. This offers a theoretical and technical framework for harmonizing water environments and urbanization in similar regions globally.

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  < 0.01) were both positively correlated with the effects of ivGC. The diagnostic accuracy of the duration of eye symptoms was ≤13 months ( p  = 0.000), with a specificity of 76.9%, and sensitivity of 65.8%. The diagnostic accuracy of the pretreatment CAS was more than 2.5 ( p  = 0.000), with a specificity of 61.5% and sensitivity of 80.5%. Besides, a multi-variables prediction model were established as well, which was better in the forecasting aspect with an area under curve of 0.784 ( p  = 0.000). Conclusions The duration of eye symptoms and restoration of euthyroidism are independent factors that are associated with the effects of ivGC. The following practical implications were inferred: firstly, the shorter the duration of eye symptoms, the more favorable the effects of ivGC therapy. Thus, prompt diagnosis and treatment (within 13 months) is important. Secondly, the restoration of euthyroidism improves the efficacy of ivGC. Thirdly, hope the multi-variables prediction model can be applied to clinical therapy in the future.

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.

Abstract 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. We investigated the TAO orbital microenvironment and observed enhancement of the Th17 cell pathway in promoting TAO development.

A male in his early 40s presented with a penetrating orbital injury after a nine-centimetre lead sinker was propelled into his right orbit while fishing. He reported pain, ptosis and visual acuity reduced to light perception. X-rays, preferred over CT due to metallic artefacts, revealed the sinker in the inferior orbital fissure with an intact eyeball. Initial surgical extraction attempts triggered a severe vagal response, necessitating endoscopic navigation for safe removal. Postoperatively, despite an intact globe, he developed vitreous haemorrhage and retinal detachment, requiring vitrectomy and silicone oil injection. Three months later, his visual acuity improved to 20/200, with normal blood lead levels. This case emphasises selecting imaging based on foreign body material, avoiding blind extraction using advanced tools if needed, monitoring for intraocular complications and assessing systemic toxicity risks.

Background Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a non-receptor tyrosine kinase that has been found to be overexpressed in various tumors. However, the role of SRMS in colorectal cancer (CRC) has not been well established. Methods We evaluated the expression levels of SRMS in CRC using GEPIA, Oncomine, and HPA datasets. Survival information and gene expression data of CRC were obtained from The Cancer Genome Atlas (TCGA). Then, the association between SRMS and clinicopathological features was analyzed using UALCAN dataset. LinkedOmics was used to determine co-expression and functional networks associated with SRMS. Besides, we used TISIDB to assess the correlation between SRMS and immune signatures, including tumor-infiltrating immune cells and immunomodulators. Lastly, protein-protein interaction network (PPI) was established and the function enrichment analysis of the SRMS-associated immunomodulators and immune cell marker genes were performed using the STRING portal. Results Compared to normal colorectal tissues, SRMS was found to be overexpressed in CRC tissues, which was correlated with a poor prognosis. In colon adenocarcinoma (COAD), the expression levels of SRMS are significantly correlated with pathological stages and nodal metastasis status. Functional network analysis suggested that SRMS regulates intermediate filament-based processes, protein autophosphorylation, translational initiation, and elongation signaling through pathways involving ribosomes, proteasomes, oxidative phosphorylation, and DNA replication. In addition, SRMS expression was correlated with infiltrating levels of CD4+ T cells, CD56dim, MEM B, Neutrophils, Th2, Th17, and Act DC. The gene ontology (GO) analysis of SRMS-associated immunomodulators and immune cell marker genes showed that they were mainly enriched in the immune microenvironment molecule-related signals. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these genes indicated that they are involved in multiple cancer-related pathways. Conclusions SRMS is a promising prognostic biomarker and potential therapeutic target for CRC patients. In particular, SRMS regulates CRC progression by modulating cytokine-cytokine receptor interaction, chemokines, IL-17, and intestinal immune networks for IgA production signaling pathways among others. However, more studies are needed to validate these findings.

AimThis study used swept-source optical coherence tomography (SS-OCT) to investigate subfoveal choroidal thickness (SFCT) in patients with thyroid-associated ophthalmopathy (TAO) who displayed different levels of disease activity and severity.MethodsThirty patients with TAO (60 eyes) and 38 healthy controls (67 eyes) in Shanghai, China, were recruited for this study. Disease activity and severity were graded using European Group on Graves’ Orbitopathy standardised criteria. SFCT values were determined by SS-OCT.ResultsIn total, 129 eyes were included in the final analysis. The mean SFCT was significantly thicker among patients with active disease (276.23±84.01 µm) than among patients with inactive disease (224.68±111.61 µm; p=0.049) or healthy controls (223.56±78.69 µm; p=0.01). There were no differences in SFCT among patients with moderate-to-severe disease, patients with severe disease and healthy controls (p>0.05). Changes in SFCT demonstrated strong predictive ability to distinguish active TAO from inactive TAO (area under the curve=0.659, 95% CI 0.496 to 0.822).ConclusionsSFCT was strongly associated with Clinical Activity Score in patients with TAO. Choroidal thickening was observed during active TAO. SS-OCT offers a non-invasive method for follow-up assessment.