ASSOCIATION BETWEEN DOME-SHAPED MACULA AND POSTERIOR STAPHYLOMA IN HIGHLY MYOPIC EYES INVESTIGATED BY ULTRA-WIDEFIELD OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To investigate the relationship between dome-shaped maculas (DSMs) and posterior staphylomas in highly myopic eyes. METHODS: Five hundred and eleven eyes of 291 patients with high myopia (refractive error ≤-8.0 diopters or axial length ≥26.5 mm) were examined by ultra-widefield swept-source optical coherence tomography (UWF-OCT). Posterior staphylomas were identified by detecting the staphyloma edges in the UWF-OCT images. RESULTS: Eighty-two eyes of the 511 highly myopic eyes had a DSM, and a posterior staphyloma was observed in 45 of 82 eyes with a DSM (54.9%) and in 301 of 429 eyes (70.2%) without a DSM. The incidence of staphylomas was significantly lower in eyes with a DSM than those without a DSM (P = 0.007). The wide macular type of staphyloma was the predominant type in eyes with a DSM (31/45 eyes; 68.9%), whereas the narrow macular type and wide macular type of staphylomas were present almost equally in the eyes without a DSM. CONCLUSION: The lack of staphylomas in 45% of eyes with a DSM suggests that DSMs form independently from posterior staphylomas. Dome-shaped maculas tend to occur in eyes with a large expansion of the posterior fundus and should be considered a posterior scleral curvature abnormality.

Whole exome sequencing combined with integrated variant annotation prediction identifies asymptomatic Tangier disease with compound heterozygous mutations in ABCA1 gene.

OBJECTIVE: Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches requires huge effort. Whole exome-sequencing (WES) has already shown approximately ∼30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective integration of many diverse annotations into a single measure (C-score) for each variant. Here, we investigated whether WES combined with integrated variant annotation prediction could facilitate the molecular diagnosis of this rare condition. METHODS: WES was performed on 8 individuals including 2 individuals exhibiting extremely low HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals as controls. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the recessive form of inheritance; 4) C-score < 10. RESULTS: Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense, or splice site variants, of which 5192 were rare (MAF ≤ 1% or not reported). Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L). CONCLUSIONS: WES combined with integrated variant annotation prediction successfully identified asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach is useful to determine causative variants, especially in recessive inherited diseases.

Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes.

Selenoprotein P (SeP; encoded by SEPP1 in humans) is a liver-derived secretory protein that induces insulin resistance in type 2 diabetes. Suppression of SeP might provide a novel therapeutic approach to treating type 2 diabetes, but few drugs that inhibit SEPP1 expression in hepatocytes have been identified to date. The present findings demonstrate that metformin suppresses SEPP1 expression by activating AMP-activated kinase (AMPK) and subsequently inactivating FoxO3a in H4IIEC3 hepatocytes. Treatment with metformin reduced SEPP1 promoter activity in a concentration- and time-dependent manner; this effect was cancelled by co-administration of an AMPK inhibitor. Metformin also suppressed Sepp1 gene expression in the liver of mice. Computational analysis of transcription factor binding sites conserved among the species resulted in identification of the FoxO-binding site in the metformin-response element of the SEPP1 promoter. A luciferase reporter assay showed that metformin suppresses Forkhead-response element activity, and a ChIP assay revealed that metformin decreases binding of FoxO3a, a direct target of AMPK, to the SEPP1 promoter. Transfection with siRNAs for Foxo3a, but not for Foxo1, cancelled metformin-induced luciferase activity suppression of the metformin-response element of the SEPP1 promoter. The overexpression of FoxO3a stimulated SEPP1 promoter activity and rescued the suppressive effect of metformin. Metformin did not affect FoxO3a expression, but it increased its phosphorylation and decreased its nuclear localization. These data provide a novel mechanism of action for metformin involving improvement of systemic insulin sensitivity through the regulation of SeP production and suggest an additional approach to the development of anti-diabetic drugs.

Graves' disease associated with infectious mononucleosis due to primary Epstein-Barr virus infection: report of 3 cases.

Although the etiology of Graves' disease is still not clear, it is generally suggested that environmental factors such as infections contribute to the development of Graves' disease. We report here three cases of Graves' disease which presented simultaneously with infectious mononucleosis due to primary EBV infection. Acute EBV infection might play an important role in the onset of Graves' disease. These three women complained of a sore throat or neck pain, resembling subacute thyroiditis. In the case of thyrotoxicosis accompanied by sore throat or neck pain, Graves' disease must be distinguished from subacute thyroiditis.