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Summary: In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium-glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications., Learning Points: While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH). NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes. SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation. A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.

Summary: A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients., Learning Points: PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes. Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations. Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

Radioactivity was measured in a micellar gel dosimeter, a polymer gel dosimeter, and water was irradiated by carbon ion beams at various beam energy conditions. Monte Carlo simulation was also performed to estimate the radioactivity. Short-lived positron-emitting nuclides were observed immediately after irradiation, but they decayed rapidly into the background. At 24 h post-irradiation, the dominant measured radioactivity was of 7 Be. The simulation also showed minor activity of 24 Na and 3 H; however, they were not experimentally observed. The measured radioactivity was independent of the type of gel dosimeter under all irradiation conditions, suggesting that the radioactivity was induced by the interaction of carbon ions with water (the main component of the gel dosimeters). The ratio between the simulated and measured radioactivity was within 0.9-1.5. The activity concentration of 7 Be was found to be less than 1/10 of the value derived using the exemption concept proposed by the International Atomic Energy Agency. This result should be applicable to irradiated gel dosimeters containing mainly water and 0-4 wt.% C and 0-1.7 wt.% N.

Competing Interests: The authors declare no conflicts of interest.

Electrocardiogram records were surveyed for the presence of an atrial premature beat (APB) and J waves in patients with coronary heart disease and patients with noncardiac diseases. The prevalence and response of J waves to sudden shortening of the RR interval on the conducted APB were determined and compared between the 2 patients groups. The change in the QRS complexes on the APB was also determined. Among 17,013 patients, 243 patients who underwent percutaneous coronary intervention for acute myocardial infarction or angina pectoris had an APB, and J waves were observed in 16 patients (6.6%). In an additional 729 patients with noncardiac diseases and APB, 19 patients showed J waves (2.6%; p = 0.010). The clinical features were almost similar between the ischemic and nonischemic groups. J waves were located more often in inferior and high lateral leads in the ischemic group. When the RR interval shortened from 942 ± 228 to 621 ± 175 ms and 869 ± 158 to 570 ± 118 ms at baseline and in the conducted APB (p<0.001 for both), the J-wave amplitude increased from 0.16 ± 0.04 to 0.19 ± 0.06 mV (p<0.001) and 0.21 ± 0.07 to 0.24 ± 0.08 mV (p = 0.010) in the ischemic and nonischemic groups, respectively. J waves in patients with chronic coronary heart disease and in patients with noncardiac diseases were augmented at short RR intervals together with distinct changes in the QRS complexes, and an augmentation of J waves at short RR interval may represent a conduction delay., (Copyright © 2019 Elsevier Inc. All rights reserved.)