Association between Sjögren syndrome, sociodemographic factors, comorbid conditions, and optic neuritis: a Taiwanese population-based study.

Purpose: Our study aimed to explore the correlation between Sjögren syndrome, sociodemographic factors, comorbid conditions, and optic neuritis. Methods: This retrospective, nationwide, population-based, matched case-control investigation involved 33,190 individuals diagnosed with optic neuritis, identified using the International Classification of Diseases, Ninth Revision, Clinical Modification codes 377.30 for optic neuritis or 377.32 for retrobulbar neuritis. Patient data were extracted from the Taiwan National Health Insurance Research Database. Demographic characteristics, the presence of Sjögren syndrome, and pre-existing comorbid conditions were analyzed using univariate logistic regression. Continuous variables were assessed with a paired t-test. Adjusted logistic regression was employed to compare the prognosis odds ratio (OR) of patients with optic neuritis to controls. Results: After adjusting for confounding variables, individuals with Sjögren syndrome exhibited a significantly higher likelihood of developing optic neuritis compared to controls (adjusted OR, 9.79; 95% confidence interval [CI], 7.28-12.98; p < 0.0001). Other conditions associated with increased odds of optic neuritis included rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, and granulomatous vasculitis (adjusted OR: 1.57, 95% CI: 1.33-1.86; adjusted OR: 2.02, 95% CI: 1.65-2.48; adjusted OR: 140.77, 95% CI: 35.02-565.85; adjusted OR: 2.38, 95% CI: 1.71-3.30; adjusted OR: 18.28, 95% CI: 2.21-151.45, respectively), as well as systemic infections such as human herpes viral infection and tuberculosis infection (adjusted OR: 1.50, 95% CI: 1.35-1.66; adjusted OR: 4.60, 95% CI: 3.81-5.56, respectively). Discussion: Our findings strongly support the existence of an association between Sjögren syndrome, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, granulomatous vasculitis, human herpes viral infection, tuberculosis, and optic neuritis.

Distinguishing spheno-orbital metastatic prostate cancer mimicking a meningioma using novel 18F-PSMA PET/CT imaging.

A 78-year-old man presented with acute-onset left temporal pain, eyelid swelling, and double vision. Computed tomography (CT) demonstrated a left sphenoid wing mass with extra-osseous intra-orbital and intracranial extension, thought to be a typical sphenoid wing meningioma by the primary team. The patient was admitted for an urgent craniotomy, which was planned for the following day. However, upon consultation with ophthalmic plastic surgery, concern was raised for an alternative diagnosis given the atypical timeline, inflammatory changes, and uncharacteristic imaging findings of mixed lytic and sclerotic bony changes without hyperostosis on CT and extensive peri-lesional dural thickening and enhancement on magnetic resonance imaging. A serum prostate-specific antigen was elevated to 206 ng/mL. Subsequent positron emission tomography (PET)/CT using 18F-fluorodeoxyglucose radiotracer was negative for metastatic disease. A prostate-specific membrane antigen (PSMA) PET/CT was then obtained and demonstrated extensive metastases. An orbital biopsy revealed poorly differentiated prostatic adenocarcinoma. The significant incongruence between the standard PET/CT and PSMA PET/CT highlights the value of this novel advanced radiographic modality in narrowing the differential diagnosis and determining the extent of disease. Findings of widespread metastasis on the PSMA PET/CT ultimately helped to avoid a large, morbid neurosurgical intervention in this patient, allowing for a minimally invasive orbital biopsy to characterize the tumor for therapeutic targeting.

Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Risk Stratification for Oropharyngeal Squamous Cell Carcinoma Using Texture Analysis on CT - A Step Beyond HPV Status.

Background and Purpose: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasingly prevalent. Despite the overall more favorable outcome, the observed heterogeneous treatment response within this patient group highlights the need for additional means to prognosticate and guide clinical decision-making. Promising prediction models using radiomics from primary OPSCC have been derived. However, no model/s using metastatic lymphadenopathy exist to allow prognostication in those instances when the primary tumor is not seen. The aim of our study was to evaluate whether radiomics using metastatic lymphadenopathy allows for the development of a useful risk assessment model comparable to the primary tumor and whether additional knowledge of the HPV status further improves its prognostic efficacy. Materials and Methods: 80 consecutive patients diagnosed with stage III-IV OPSCC between February 2009 and October 2015, known human papillomavirus status, and pre-treatment CT images were retrospectively identified. Manual segmentation of primary tumor and metastatic lymphadenopathy was performed and the extracted texture features were used to develop multivariate assessment models to prognosticate treatment response. Results: Texture analysis of either the primary or metastatic lymphadenopathy from pre-treatment enhanced CT images can be used to develop models for the stratification of treatment outcomes in OPSCC patients. AUCs range from .78 to .85 for the various OPSCC groups tested, indicating high predictive capability of the models. Conclusions: This preliminary study can form the basis multi-centre trial that may help optimize treatment and improve quality of life in patients with OPSCC in the era of personalized medicine.

Case Report: Allogenic Simple Limbal Epithelial Transplantation From a Human Leukocyte Antigen-Matched Living Related Donor to Treat Bilateral Corneal Chemical Burns Post Laser-Assisted in situ Keratomileusis.

A 35-year-old woman who had undergone laser-assisted in situ keratomileusis in both eyes experienced bilateral total limbal stem cell deficiency (LSCD) due to chemical burns. Due to bilateral severe LSCD, allogenic simple limbal epithelial transplantation (SLET) from a human leukocyte antigen (HLA)-matched living related donor was the first choice of treatment for her left eye. We report the first case of HLA or ABO matching living related allogenic SLET for permanent restoration of the cornea for bilateral LSCD treatment. Our ABO-HLA-matched living related allogenic SLET alleviation of the systemic immunosuppressant to topical corticosteroids alone. It also came the limitations of prolonged systemic immunosuppressant usage in conjunctival-limbal allografts and keratolimbal allograft.

Associations between Sjögren Syndrome, Sociodemographic Factors, Comorbid Conditions, and Scleritis in a Taiwanese Population-Based Study.

This nationwide, population-based, retrospective, matched case-control study included 111,960 newly diagnosed patients with scleritis who were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification code 379.0, selected from the Taiwan National Health Insurance Research Database. Demographic characteristics, Sjögren syndrome, and comorbid conditions within 1 year before the scleritis diagnosis were examined using univariate logistic regression analyses, and a paired t-test was used for continuous variables. Adjusted logistic regression was used to compare the prognosis odds ratio (OR) of the patients with scleritis with the controls. After adjustment for confounders, patients with Sjögren syndrome were remarkably more likely to have scleritis than the controls (OR = 33.53, 95% confidence interval (CI) = 27.43-40.97, p < 0.001). Other conditions found to have increased odds of scleritis included post ocular pterygium, glaucoma, and scleral surgery (OR = 4.01, 95% CI = 3.64-4.43; OR = 3.16, 95% CI = 2.24-4.47; OR = 6.83, 95% CI = 5.34-8.74, respectively); systemic infections, such as syphilis, tuberculosis, and a human herpes viral infection (OR = 4.01, 95% CI = 2.93-5.50; OR = 2.24, 95% CI = 1.94-2.58; OR = 8.54, 95% CI = 8.07-9.03, respectively); and systemic diseases, such as rheumatoid arthritis, granulomatous vasculitis, systemic lupus erythematosus, ankylosing spondylitis, and gout (OR = 2.93, 95% CI = 2.66-3.23; OR = 7.37, 95% CI = 3.91-13.88; OR = 3.18, 95% CI = 2.63-3.85; OR = 5.57, 95% CI = 4.99-6.22; OR = 2.84, 95% CI = 2.72-2.96, respectively). The results strongly support an association between Sjögren syndrome, post ocular surgery, systemic infection disease, systemic autoimmune disease, and scleritis.

Posterior Skull Base Anatomy and Pathology.

A posterior skull base lesion is an uncommon radiological finding that may be noted incidentally or during targeted imaging of patients with clinical symptoms attributable to the lesion. It may be inflammatory or neoplastic in etiology, or may simply be an anatomic variant or a "don't-touch" lesion that should not be misinterpreted as something more ominous. A systematic approach to the evaluation of the posterior skull base is therefore required in order to differentiate lesions requiring immediate attention from those requiring a less urgent course of action or none at all. This review will focus on the imaging features of pathologic conditions that are more commonly encountered in posterior skull base CT and MR examinations.

Monounsaturated oleic acid modulates autophagy flux and upregulates angiogenic factor production in human retinal pigment epithelial ARPE-19 cells.

AIMS: Dyslipidemia-associated diabetic retinopathy is featured by macular edema and retinal angiogenesis. This study investigated the in vitro lipotoxicity of free fatty acids and their modulatory roles in regulation of autophagy and angiogenic factor production in cultured human retinal pigment epithelium (RPE) ARPE-19 cells. MAIN METHODS: ARPE-19 cells were exposed to monounsaturated oleic acid (OA), saturated palmitic acid (PA), or both. Cell viability, cell cycle distribution, migration, and autophagy of the treated cells were monitored. Angiogenic factor production was determined by RT-qPCR and ELISA. KEY FINDINGS: OA, but not PA, at doses higher than 500 µM significantly induced cytostasis and lipotoxicity in ARPE-19 cells. OA exposure not only markedly enhanced autophagy flux, but also enhanced cell migration, while PA suppressed motility of RPE cells. Meanwhile, OA stimulated de novo synthesis of angiogenic factors including VEGF and bFGF in ARPE-19 cells. Mechanistically, OA treatment stimulated not only AMPK/mTOR/p70S6K signaling, but also induced hyperphosphorylation of MAPK pathway mediators, including ERK, JNK and p38 MAPK, as well as NF-κB activation. Kinase inhibition assays showed that blockade of PI3K/Akt, MAPK and NF-κB pathways prevented the OA-upregulated VEGF transcription and its peptide release. Comparatively, only NF-κB inhibition significantly suppressed bFGF peptide release from ARPE-19 cells. SIGNIFICANCE: Out findings support the OA-exhibited cytostasis, autophagy modulation and angiogenic factor production in RPE cells. This study sheds light on the interrelationship between metabolic disorder and retinopathy and provides molecular strategies for preventing and treating choroidal neovascularization in diabetic retinopathy.

Increased risk of central serous chorioretinopathy following end-stage renal disease: A nationwide population-based study.

This retrospective, nationwide, matched cohort study investigated the risk of central serous chorioretinopathy (CSCR) following end-stage renal disease (ESRD). The study cohort included 84722 ESRD patients who were registered between January 2000 and December 2009 at the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 84722 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. We collected information for each patient from the index date until December 2011. During the follow-up period, we found a significantly elevated risk of CSCR in the ESRD patients compared with controls (incidence rate ratio = 1.51, 95% confidence interval = 1.24-1.84). After adjustment for potential confounders, including age, sex, coronary artery disease, peptic ulcer, and obstructive sleep apnea, ESRD patients were 1.41 times more likely to develop CSCR (adjusted hazard ratio = 1.41, 95% confidence interval = 1.14-1.73). In conclusion, we found that ESRD patients showed a significantly higher risk of developing CSCR and recommend regular retina examinations and education regarding CSCR for patients with ESRD.

All-trans retinoic acid suppresses the adhering ability of ARPE-19 cells via mitogen-activated protein kinase and focal adhesion kinase.

This study investigated the signaling mechanism underlying the anti-adhesive effect of all-trans retinoic acid (ATRA) on retinal pigment epithelial ARPE-19 cells. Adhesion kinetics with or without ATRA treatment were profiled by adhesion assay. Surface coating with type IV collagen, fibronectin, laminin, but not type I collagen, significantly enhanced adhesion and spreading of ARPE-19 cells, while ATRA at subtoxic doses (ranging from 10-7 to 10-6 M) profoundly suppressed the extracellular matrix-enhanced adhesion ability. Cell attachment on FN activated PI3K/Akt and MAPK cascades, whereas ATRA pretreatment blunted the early phosphorylation of Akt and MAPK signaling mediators including p38 MAPK, JNK1/2, and ERK1/2. Mechanistically, signaling blockade with selective kinase inhibitors demonstrated that all MAPK pathways were involved in the anti-adhesive effect of ATRA, whereas the PI3K inhibitor treatment significantly potentiated the ATRA-suppressed RPE cell adhesion. Moreover, ATRA treatment did not affect intracellular F-actin distribution, but remarkably reduced focal adhesion kinase (FAK) expression and its nuclear localization during ARPE-19 cell attachment. In conclusion, ATRA suppresses the adhering ability of ARPE-19 cells at least in part through MAPK and FAK pathways. Signaling blockade with PI3K inhibitor could be regarded as an alternative modality for treating proliferative vitreoretinopathy.

RISK OF RETINAL VEIN OCCLUSION WITH CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To investigate the risk of retinal vein occlusion (RVO) after central serous chorioretinopathy (CSCR). METHODS: The study included 2882 CSCR patients and 17,292 control patients matched by age, sex, number of visits to an ophthalmologist, diabetes mellitus, hypertension, and hyperlipidemia from January 2001 to December 2010 from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected until December 2011. Cox proportional hazard regression analysis was used to obtain the adjusted hazard ratio for RVO. The RVO-free survival rate was calculated using Kaplan-Meier analysis. RESULTS: There was a significantly higher risk of RVO in CSCR patients than in controls (incidence rate ratio = 3.07, 95% confidence interval = 1.86-5.07). After adjustment for potential confounders, the adjusted hazard ratio for developing RVO in the CSCR patients was 3.15 times higher than that of the controls (adjusted hazard ratio = 3.15, 95% confidence interval = 1.91-5.21). CONCLUSION: Central serous chorioretinopathy increases the risk of RVO. For CSCR patients, the authors recommend thorough retinal vessel evaluation, regular follow-up, and education regarding RVO for patients with CSCR.

Mediator Subunit Med28 Is Essential for Mouse Peri-Implantation Development and Pluripotency.

The multi-subunit mammalian Mediator complex acts as an integrator of transcriptional regulation by RNA Polymerase II, and has emerged as a master coordinator of development and cell fate determination. We previously identified the Mediator subunit, MED28, as a cytosolic binding partner of merlin, the Neurofibromatosis 2 (NF2) tumor suppressor, and thus MED28 is distinct in having a cytosolic role as an NF2 interacting protein as well as a nuclear role as a Mediator complex subunit. Although limited in vitro studies have been performed on MED28, its in vivo function remains unknown. Employing a knockout mouse model, we describe for the first time the requirement for Med28 in the developing mouse embryo. Med28-deficiency causes peri-implantation lethality resulting from the loss of pluripotency of the inner cell mass accompanied by reduced expression of key pluripotency transcription factors Oct4 and Nanog. Further, overexpression of Med28 in mouse embryonic fibroblasts enhances the efficiency of their reprogramming to pluripotency. Cre-mediated inactivation of Med28 in induced pluripotent stem cells shows that Med28 is required for their survival. Intriguingly, heterozygous loss of Med28 results in differentiation of induced pluripotent stem cells into extraembryonic trophectoderm and primitive endoderm lineages. Our findings document the essential role of Med28 in the developing embryo as well as in acquisition and maintenance of pluripotency during reprogramming.

Retinal artery occlusion and the 3-year risk of stroke in Taiwan: a nationwide population-based study.

PURPOSE: To verify the association between retinal artery occlusion (RAO) and stroke with a large-scale nationwide study. DESIGN: Retrospective nationwide population-based administrative database study. METHODS: Data were collected from the Longitudinal Health Insurance Database 2000 (LHID2000), which contains claim data from 1 million randomly selected beneficiaries among Taiwan's 23 million residents. The study cohort consisted of all patients with a diagnosis of RAO from January 1999 through December 2006 (n = 464). The control group consisted of randomly selected patients (n = 2748) matched with the study group by age, sex, date of index medical care, and comorbid hypertension. Patients were tracked from their index date for 3 years. The Kaplan-Meier method was used to compute the stroke-free survival rate. Cox proportional hazard regressions were used to compute the adjusted stroke-free survival rate after adjusting for possible confounding factors. RESULTS: Ninety-one RAO patients (19.61%) and 280 controls (10.05%) had a stroke (P < .0001) during the 3-year follow-up period. Compared with the controls, the incidence rate ratios of stroke in RAO patients were 9.46 at 0-1 month, 5.57 at 1-6 months, and 2.16 at 0-3 years after RAO (P < .0001). After adjusting for age, sex, and selected comorbid disorders, the hazard ratio of having a stroke for RAO patients was still 2.07 times higher than that of controls and 3.34 times higher in the ≤60-year-old subgroup. CONCLUSIONS: RAO increases the risk for subsequent stroke. Early neurologic evaluation and secondary prevention for stroke are recommended for RAO patients.

Mutational analysis of the autoprocessing site of subtilisin YaB-G124A.

The potential residue at the autoprocessing site for improving processing efficiency was evaluated from hydrolysis of 19 cleavage-site-mimicking octapeptides, VTTXQTVP (-4 to +4), by the mature subtilisin YaB and YaB-G124A mutants. Both enzymes cleaved the octapeptides mainly at two sites, X-Q (A-site) and Q-T (B-site), at varied preferences. Based on the results above, Met(-1) of YaB-G124A was mutated and, as expected, extracellular enzyme production increased with Gln or Ala replacement, but decreased with Ile or Asp substitution. Together with previous structural studies, our results suggest that autoprocessing is dependent on not only the primary structure, but also the peptide flexibility around the processing site. Cleavage at the B-site resulted in a novel YaB mutant lacking the N-terminus Gln 1, which led the mutant enzyme to less enzymatic activity by 80% and less thermal stability by 20 degrees C, perhaps due to its ligation to the high-affinity calcium ion.