Determining the Location of the Fovea Centralis Via En-Face SLO and Cross-Sectional OCT Imaging in Patients Without Retinal Pathology.

Purpose: The purpose was to establish the position of the fovea centralis to the optic nerve via en-face, near-infrared spectral domain optical coherence tomography (NIR-OCT) in healthy patients. This may shed light on physiological variability and be used for studying subtle cases of foveal ectopia in macular pathology and after retinal detachment. Methods: SD-OCT data of 890 healthy eyes were retrospectively analyzed. Exclusion criteria included axial myopia causing tilting of the optic disc, peripapillary atrophy >1/3 the width of the disc, macular images excluding greater than half of the optic disc, and patients unable to maintain vertical head positioning. Two independent reviewers measured the horizontal and vertical distance from the fovea to the optic disc center and optic disc diameter via cross-sectional and en-face scanning laser ophthalmoloscopy OCT imaging. Results: 890 eyes were included in the study. The right and left eyes differed in the horizontal distance from the fovea to the disc center (4359 vs. 4248 µm, P < 0.001) and vertical distance from the fovea to the disc center (464 µm vs. 647, P < 0.001). This corresponded to a smaller angle between the right and left eyes (6.07° vs. 8.67°, P < 0.001). Older age was associated with a larger horizontal (P = 0.008) and vertical distance (0.025). These differences persisted after correcting for axial length in the 487 patients with axial-length data. Conclusions: This study compares the position of the fovea centralis among individuals without macular pathology on a micron level basis. The significant variability between right and left eyes indicates that contralateral eye evaluation cannot be reliably used. Rather, true foveal ectopia requires assessments of preoperative and postoperative NIR-OCT scans. This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia. Translational Relevance: This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia.

Predictors of Universal Catheter Failure in Transradial Coronary Angiography.

BACKGROUND: Use of a universal diagnostic catheter may decrease procedural time and catheter-exchange related spasm when compared with a dual-catheter strategy. The aim of this study was to identify preprocedural predictors of failure to complete a coronary angiogram with a universal catheter alone. METHODS: Consecutive patients (n = 782) who underwent a right transradial/transulnar coronary angiogram with a single operator were retrospectively reviewed. Multivariable predictors of failure to complete the procedure with a universal catheter alone were identified using logistic regression analysis and presented as odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of the study population (n = 558), a total of 216 (38.7%) required exchange to a coronary-specific catheter (44.4% for right coronary artery alone, 25.5% for left coronary artery alone, 30.1% for both) and 342 (61.3%) underwent angiography with a universal catheter alone. Patients who required a catheter exchange were more likely to have the following characteristics compared with patients who underwent an angiogram with a universal catheter alone: age >75 years (27.3% vs 16.4%; P<.01), female sex (34.3% vs 23.1%; P<.01), diabetes mellitus (50.0% vs 38.3%; P<.01), hypertension (88.0% vs 74.6%; P<.001), and chronic kidney disease (29.2% vs 17.8%; P<.01). After multivariable adjustment, age ≫75 years (OR, 1.92; 95% CI, 1.21-3.04), female sex (OR, 1.94; 95% CI, 1.20-3.14), hypertension (OR, 2.08; 95% CI, 1.22-3.57), and chronic kidney disease (OR, 1.58; 95% CI, 1.01-2.46) predicted failure of a universal catheter alone to complete angiography. CONCLUSION: Consideration may be given to use an initial dual-catheter strategy if one or more of the following are present: elderly age, female sex, hypertension, and chronic kidney disease.

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis.

Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)- and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As2O3), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As2O3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As2O3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As2O3-induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.

Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency.

Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency.