Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology.

Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases.

Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival.

Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 (PDIA-4); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFß-signaling, and inhibition of TGFß-signaling suppressed EndMT in PDIA-4-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.

Retrobulbar Optic Neuritis Post Typhoid fever: Atypical Case Report.

Purpose: Post typhoid autoimmune-mediated simultaneous retrobulbar optic neuritis (RBN) involving both eyes is a rare complication requiring early diagnosis and prompt treatment. Case presentation: We present a case of bilateral RBN in a six-year-old male who came to our department with a chief complaint of sudden onset painless profound loss of vision in both eyes, after an episode of high-grade fever 2 weeks earlier. Perception of light was doubtful in right eye (RE) and vision was hand movement in left eye (LE). On ocular examination, anterior segment and fundoscopy of both eye were normal. Blood investigation was normal except for raised ESR. CT of brain and orbit was normal. MRI of brain and orbit revealed bilateral thickening and restriction of optic nerve suggestive of ON. He was initiated with intravenous methyl-prednisolone for three consecutive days after which tapering doses of oral corticosteroid was given. Results: A rapid and marked improvement in Uncorrected Visual Acuity (UCVA) was observed with UCVA improving to 6/ 12 RE and 6/ 9 LE post 1 month. The pupillary reaction also became normal in both eyes. Moreover, there was a significant reduction in the Widal titre of the patient post 2 weeks of treatment. Discussion: Paediatric ON has rare and unique characteristics, which differentiates it from adult ON. No clinical trials have been performed for paediatric ON, so current clinical practice follows the evidence drawn from the Optic Neuritis Treatment Trial (ONTT). Conclusion: Paediatric ON is uncommon. Despite having clinically severe bilateral vision loss, retrobulbar optic neuritis in children post typhoid fever has excellent response to steroid therapy if early diagnosed and treated. Abbreviations: RBN = Retrobulbar Optic Neuritis, MRI = Magnetic Resonance Imaging, CT = Computerized Tomography, UCVA = Uncorrected Visual Acuity, RE = Right eye, LE = Left eye, ON = Optic neuritis, ONTT = Optic Neuritis Treatment Trial.

Prevalence of dry eye, its categorization (Dry Eye Workshop II), and pathological correlation: A tertiary care study.

Purpose: To study the prevalence of dry eye disease (DED), further categorize using DEWS II protocol, grade squamous metaplasia in each group, and determine associated risk factors in a tertiary care hospital. Methods: This cross-sectional hospital-based study screened 897 patients ≥30 years via systematic random sampling. Patients with both symptoms and signs as defined by the Dry Eye Workshop II protocol were considered as DED, further categorized, and subjected to impression cytology. Categorical data were assessed using the Chi-square test. P value < 0.05 was considered statistically significant. Results: In total, 265 (of 897) patients were defined as DED based on the presence of symptoms (DEQ-5 ≥6) and at least one positive sign (fluorescein breakup time [FBUT] <10 s or OSS ≥4). DED prevalence was thus 29.5% with aqueous deficient dry eye (ADDE), evaporative dry eye (EDE), and mixed type seen in 92 (34.71%), 105 (39.62%), and 68 (25.7%) patients, respectively. The risk of developing dry eye was higher in the age above 60 years (33.74%) and in the third decade. Females, urban dwellers, diabetics, smokers, history of previous cataract surgery, and usage of visual display terminal devices were found to be significantly associated with risk factors of DED. Squamous metaplasia and goblet cell loss were more severe in mixed compared to EDE and ADDE. Conclusion: Hospital-based prevalence of DED is 29.5% with a preponderance of EDE (EDE 39.62%, ADDE 34.71%, and mixed 25.71%). A higher grade of squamous metaplasia was seen in the mixed type compared to other sub-types.