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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.)

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 μg/kg/min (normal dose) and 170 μg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

A 74-year-old male suffering from congestive heart failure with atrial tachycardia (AT) with 2 : 1 atrioventricular conduction was admitted to our hospital. After the therapy with diuretics and β -blocker, his rapid AT was still sustained. He took the catheter ablation for his AT. Postpacing interval mapping from entrainment and noncontact mapping system revealed the mechanism of his AT, originated from sinus venosa. His AT was successfully terminated and eliminated by radiofrequency catheter ablation. After the successful ablation, he has been free from any AT, and his cardiac function was also improved.

Purpose: Depression has a high recurrence rate among employees. There have been few studies investigating risk factors for recurrent sickness absence due to depression after return to work (RTW). The objective of this study was to identify potential risk factors., Methods: Subjects were 540 full-time employees at the biggest telecommunication company in Japan who returned to work from April 2002 to March 2008 after their first leave of absence due to depression. The Cox proportional hazard model was employed to find risk factors for recurrent sickness absence by analyzing variables including demographic, work-related and work environmental factors., Results: Of 540 study subjects, 200 employees (37.0 %) experienced recurrent sickness absence due to depression after RTW within the follow-up period. Higher organizational job demand evaluated by the Brief Job Stress Questionnaire (BJSQ) was found to be a risk factor (OR 1.46, 95 % CI 1.01-2.10) for recurrent sickness absence due to depression adjusted for confounding factors., Conclusions: High organizational job demand (evaluated by BJSQ) is a risk factor for recurrent sickness absence due to depression after RTW.

There have been few epidemiological studies on recurrent sickness absence due to depression after returning to work (RTW). The objective of this study was to investigate the prognosis of workers who are RTW with depression in a Japanese company. This study employed a descriptive epidemiology study design. Subjects of this study were 540 employees who worked full-time and were registered in the Health Data System and returned to work from April 2002 to March 2008 after their first leave of absence due to depression. We investigated the recurrence of sickness absence due to depression after returning to work using the Kaplan-Meier survival curve method. During the 8.5 yr follow-up period, almost half of the RTW employees experienced recurrent sickness absence. There was a steep increase in recurrent rates the first two years after RTW, and 85.2% of total recurrence of sickness absence had occurred within three years after the index episode.

Background: How coronary distensibility contributes to stable or unstable clinical manifestations remains obscure. We postulated that the heterogeneous plaque distensibility is associated with unstable clinical presentations in patients with acute coronary syndrome (ACS)., Methods and Results: Seventeen and 19 ACS-related and -unrelated lesions, respectively, were visualized using intravascular ultrasound imaging with simultaneous intracoronary pressure recording. Systolic and diastolic lumen cross-sectional areas were measured at the lesion site and at five evenly spaced sites between the proximal and distal reference sites. The coronary distensibility index and stiffness index β were calculated for each site and averaged for each coronary segment. Maximal distensibility index, standard deviation and the difference between maximal and minimal distensibility indices within each segment were significantly higher in the ACS-related than -unrelated plaques (5.6 ± 2.3 vs. 3.7 ± 1.8, p < 0.001, 2.1 ± 0.9 vs. 1.1 ± 0.6, p < 0.001 and 5.3 ± 2.3 vs. 2.8 ± 1.5, p < 0.001, respectively). Moreover, the difference in the distensibility index between the lesion site of ACS-related plaques and the immediate proximal site was significantly larger (2.88 ± 2.35 vs. 1.17 ± 1.44, p = 0.022) than that in ACS-unrelated plaques., Conclusions: Coronary artery distensibility is longitudinally more heterogeneous in ACS-related than-unrelated plaques, especially between the lesion and the immediate proximal site.

We studied the effect of fluoroquinolones (FQs) on carrageenan-induced edema in the rat footpad. Ciprofloxacin, gatifloxacin, sparfloxacin, norfloxacin, and enoxacin (s.c., 100 mg/kg), which have piperazinyl and/or cyclopropyl groups, inhibited carrageenan-induced edema, whereas levofloxacin, tosufloxacin, and pazufloxacin did not. The reduction of edema by ciprofloxacin, sparfloxacin, and enoxacin was abolished by pretreatment with mifepristone, an antagonist of the glucocorticoid receptor. These results suggest that FQs with piperazinyl and/or cyclopropyl groups can modify biological responses through enhancing the glucocorticoid-glucocorticoid receptor system.

Preventing left ventricular (LV) remodeling after coronary artery bypass graft surgery (CABG) is important to avoid long-term congestive heart failure. The present study evaluated the effects of angiotensin converting enzyme inhibitors (ACEIs) and beta-blockers on LV remodeling. Twenty-three patients with angina pectoris and 36 with old myocardial infarction underwent CABG. We assessed end diastolic volume index (EDVI), end systolic volume index (ESVI), and ejection fraction (EF) using left ventriculography before and after CABG. Changes in EDVI, ESVI, and EF were studied in the ACEI, beta-blocker, and control groups. Although EDVI was reduced in the ACEI group, ESVI and EF improved only slightly, whereas in the group given beta-blockers, ESVI was reduced, EF improved, and EDVI was minimally reduced. These results indicate that ACEIs and beta-blockers both protect against LV remodeling, although through different mechanisms.

Objective: The purpose of this study was to assess the value of multiarterial phase contrast-enhanced dynamic MRI of the whole liver obtained during a single breath-hold for small early enhancing hepatic lesions in patients with cirrhosis or chronic hepatitis, emphasizing the distinction between hypervascular hepatocellular carcinomas and pseudolesions., Materials and Methods: The study population included 40 patients with cirrhosis or chronic hepatitis who had small early enhancing hepatic lesions (a total of 70 lesions: 40 hepatocellular carcinomas, 30 pseudolesions). All patients underwent multiarterial phase contrast-enhanced dynamic MRI (six phases) of the whole liver during a single breath-hold., Results: Twenty-one (53%) of 40 hypervascular hepatocellular carcinomas showed rapid central washout after early enhancement of the lesion as well as peritumoral coronal enhancement, but these findings were not observed in any hypervascular pseudolesions (p < 0.001). In 19 hepatocellular carcinomas without rapid central washout, early enhancement of the lesion appeared at the second, third, or fourth phase (mean, 2.5 phases). In eight of these 19 hepatocellular carcinomas, lesion enhancement disappeared by the sixth phase. Conversely, in 30 hypervascular pseudolesions, early enhancement of the lesion appeared at the second, third, fourth, or fifth phase (mean, 3.0 phases). In 28 of these 30 pseudolesions, lesion enhancement continued until the sixth phase., Conclusion: Rapid central washout after the early enhancement of the lesion and coronal enhancement surrounding the lesion are highly specific and diagnostic findings of small hypervascular hepatocellular carcinomas if present at multiarterial phase contrast-enhanced dynamic MRI. Hypervascular pseudolesions tend to show prolonged enhancement during the arterial phase compared with hypervascular hepatocellular carcinomas.

To assess the roles of vascular prostaglandins in the hypertension of chronic renal failure, the release of prostacyclin and thromboxane (TX) from aorta was evaluated in male Sprague-Dawley rats, the renal mass of which was reduced by removing one kidney and two-thirds of the contralateral kidney ("5/6 nephrectomy"). Five-sixths nephrectomy was followed by significant rises in serum creatinine to 0.55 +/- 0.03 mg/dl and urea nitrogen to 42.9 +/- 3.8 mg/dl, with a concomitant rise in mean blood pressure from 121.6 +/- 1.6 mmHg to 155.3 +/- 8.4 mmHg. In 5/6 nephrectomized rats, the release of TX A2 from aorta, as measured by its stable metabolite TX B2, increased by 60% (p less than 0.01) and prostacyclin, as measured by its stable metabolite 6-keto-prostaglandin, F1 alpha (6-keto-PG F1 alpha) increased by 51% (p less than 0.05). The amounts of both TX B2 and 6-keto-PG F1 alpha released from aorta were closely related to the height of mean blood pressure. These results suggest that the enhanced vasoconstrictor TX production in the vascular walls may be relevant to hypertension in rats with subtotal renal ablation. The adaptive increase in prostacyclin production in the vascular walls may compensate for the elevation of blood pressure due to chronic renal failure in this animal model.

The validity of the Giusti-Hayton method for dosage regimen adjustment in patients with renal impairment was investigated using ranitidine. Five normal healthy volunteers received a single ranitidine recommended dose of 150 mg, and 20 patients with renal disease received single administration in doses individually calculated by the Giusti-Hayton method from each patient's creatinine clearance level, and the various pharmacokinetic parameters were compared. As a result, the area under the time-concentration curve 0----infinity (AUC0----infinity) in the renal disease patients was almost comparable to that in the normal healthy volunteers. The Giusti-Hayton method was considered useful to keep both the AUC0----infinity constant and the mean blood level of the drug in a steady state, in any degree of renal impairment.

Effects of guanfacine, a centrally acting antihypertensive, on blood pressure, heart rate, plasma renin activity, serum aldosterone, plasma norepinephrine, and renal function were evaluated in 16 patients with hypertension with biopsy-proved chronic glomerulonephritis. Guanfacine monotherapy with a daily dose of 1 to 2.5 mg at bedtime for 6 months brought about a significant reduction in blood pressure (171 +/- 2/110 +/- 2 to 144 +/- 2/89 +/- 1 mm Hg; P less than 0.01), with concurrent decreases in heart rate (78 +/- 2 to 70 +/- 2 bpm; P less than 0.01), plasma renin activity (1.96 +/- 0.12 to 1.21 +/- 0.19 ng/ml/hr; P less than 0.05), aldosterone (14.6 +/- 1.5 to 9.7 +/- 0.9 ng/dl; P less than 0.05), plasma norepinephrine (220.5 +/- 24.2 to 132.8 +/- 27.7 pg/ml; P less than 0.05). There was no change in serum creatinine, beta 2-microglobulin, or endogenous creatinine clearance during guanfacine monotherapy. Our data suggest that guanfacine exerts its antihypertensive effect via the inhibition of sympathetic outflow and in part the suppression of the reninangiotensin-aldosterone system and that guanfacine is suitable for the effective treatment of hypertension associated with chronic glomerulonephritis.

In a 42-year-old man with severe hypertension, stenosis of the left renal artery at its origin and occlusion of the abdominal aorta below the level of the renal arteries were observed. His past history and clinical and laboratory findings suggested that the renal artery stenosis was due to Buerger's disease which was reported to be a rare cause of renovascular hypertension.

To clarify the role of the sympathetic nervous system in the development of hypertension in chronic renal failure, plasma levels and urinary excretions of catecholamines were evaluated in male Sprague-Dawley rats. The renal mass of the rats was reduced by removing one kidney and two-thirds of the contralateral kidney (5/6 nephrectomy). Five-sixths nephrectomy was followed by significant increases in serum creatinine (to 0.55 +/- 0.03 mg/dl) and urea nitrogen (to 42.9 +/- 3.8 mg/dl). There was a concomitant increase in mean blood pressure, measured directly by an implanted aortic catheter, in comparison with control rats (155.3 +/- 8.3 versus 123.6 +/- 3.3 mmHg, P less than 0.01). Both plasma levels and urinary excretion of norepinephrine and epinephrine were elevated in the 5/6-nephrectomized rats compared with controls. Mean blood pressure correlated negatively with 24-h creatinine clearance (r = -0.66, P less than 0.05), and positively with plasma norepinephrine (r = 0.83, P less than 0.01) and urinary excretion of norepinephrine (r = 0.63, P less than 0.05). These results suggest that not only the decrease in renal function, but also hyperactivity of the sympathetic nervous system, may be involved in the pathogenesis of hypertension in rats with subtotal renal ablation.

The ratio of the plasma level of beta-thromboglobulin (beta-TG) to platelet factor 4 (PF-4) which is regarded as a most reliable indicator of platelet activation in vivo, was followed in 52 subjects at various stages of essential hypertension according to the WHO classification. These comprised 30 cases at stage I, 19 cases at stage II and three cases at stage III, and 20 age-matched normotensive control subjects. The observed beta-TG:PF-4 ratio in the hypertensive patients was 4.59 +/- 0.20, which was significantly higher than the value of 3.13 +/- 0.19 recorded in the normotensive control subjects. According to the WHO classification, beta-TG:PF-4 ratios in hypertensive patients at stages I, II and III were 3.93 +/- 0.19, 5.31 +/- 0.35 and 6.56 +/- 0.12, respectively. The beta-TG:PF-4 ratio revealed a tendency of platelet activation to increase with advanced progress of hypertensive vascular lesions. These results suggest that the abnormal platelet function observed in patients with essential hypertension plays an important role in the development of hypertensive vascular complications.

The effects of sodium intake on blood pressure and platelet function were evaluated in 19 subjects with essential hypertension (10 men and 9 women; mean age 49.7 years). The study was conducted under 3 conditions: (1) normal sodium diet (12 g/day of salt was used in cooking), (2) after 5 days of mild sodium restriction diet (6 g/day of salt was used in cooking) and (3) after moderate sodium restriction (no salt was used in cooking). Blood pressure was significantly reduced following sodium restriction without any change in heart rate. The ratio of the plasma level of beta-thromboglobulin to platelet factor IV, regarded as the most reliable index for platelet activation in vivo, increased significantly after mild sodium restriction; this change was maintained after moderate sodium restriction. Plasma thromboxane B2, a stable metabolite of thromboxane A2, increased significantly after sodium restriction; the level of 6-ketoprostaglandin F1 alpha, a stable metabolite of prostacyclin, was unaffected. These results indicate that dietary sodium restriction induces both a reduction of blood pressure and an activation of platelet function in vivo. Thus, one must consider both antihypertensive effects and effects on platelet function as factors in adjusting the dietary sodium intake in the course of antihypertensive therapy.

This report describes a 45-year-old man who suffered from hemolytic-uremic syndrome. In his autopsy findings, kidney arteriolar walls showed marked hyaline degeneration and interlobular arteries were occluded by severe intimal proliferation. No vascular changes were found in other organs. There were no arteriosclerotic changes in either main branches from the aorta or the aorta. These vascular changes are correspond well with the early features of malignant nephrosclerosis without any clinical findings of malignant hypertension. This type is called primary malignant nephrosclerosis by Bohle et al. We would like to point out the significance of this case in the re-consideration of the pathogenesis of malignant nephrosclerosis.

A crossover study was planned in order to compare the effects of captopril and slow channel calcium entry blocker (Ca antagonist) on urinary protein excretion in 7 hypertensive patients with renal diseases, including 4 with IgA nephropathy, 2 with lupus nephritis and 1 with benign nephrosclerosis. Captopril decreased urinary protein excretion by 52% without any change in creatinine clearance, while Ca antagonist was having a slight effect on proteinuria even though the drug showed an equivalent antihypertensive effect as captopril. These results suggest that the attenuation of proteinuria induced by captopril may be related to an inhibition of angiotensin II formation and/or a direct action of this drug on protein permeability of glomerular basement membrane.

Gas chromatography-mass spectrometry was employed to identify the two volatile amines in male mouse urine. These amines were much less concentrated in urine of castrated males. The identified amines, isobutylamine and isoamylamine, were assayed for the potential of puberty acceleration in postweaning female mice. A total of 105 young female mice were exposed to one of the following five odors: distilled water (control), 0.1 M isobutylamine, 0.1 M isoamylamine, a mixture of 0.05 M isobutylamine and 0.05 M isoamylamine, or fresh male mouse urine. The mixture of these amines accelerated the vaginal opening of young females. Except for the control, all experimental odors accelerated the first vaginal estrus in ICR strain mice.