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Metabolic syndrome (MetS) is cluster of metabolic diseases, including abdominal obesity, hyperglycemia, high blood pressure, and dyslipidemia, that directly escalate the risk of type 2 diabetes, heart disease, and stroke. Thioredoxin-interacting protein (TXNIP) is a binding protein for thioredoxin, a molecule that is a key inhibitor of cellular oxidation, and thus regulates the cellular redox state. Epigenetic alteration of the TXNIP-encoding locus has been associated with components of MetS. In the present study, we sought to determine whether the level of TXNIP methylation in blood is associated with MetS in the general Japanese population. DNA was extracted from the peripheral blood cells of 37 subjects with and 392 subjects without MetS. The level of TXNIP methylation at cg19693031 was assessed by the bisulfite-pyrosequencing method. We observed that TXNIP methylation levels were lower in MetS subjects (median 74.9%, range 71.7-78.4%) than in non-MetS subjects (median 77.7%, range 74.4-80.5%; p = 0.0024). Calculation of the confounding factor-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for hypomethylation revealed that subjects with MetS exhibited significantly higher ORs for hypomethylation than did those without MetS (OR, 2.92; 95% CI, 1.33-6.62; p = 0.009). Our findings indicated that lower levels of TXNIP methylation are associated with MetS in the general Japanese population. Altered levels of DNA methylation in TXNIP at cg19693031 might play an important role in the pathogenesis of ‍MetS.

Some studies have demonstrated that excessive fructose consumption negatively impact brain function. Recently, the Developmental Origins of Health and Disease hypothesis - which suggests that maternal nutritional status during gestation and lactation can alter offspring phenotype - has received much attention. In a previous study, we demonstrated that maternal fructose consumption increases levels of lipid peroxides in hippocampi of offspring. The hypothesis in the present study was that maternal fructose intake would affect hippocampal antioxidant enzyme via epigenetic regulation. Upon confirmation of gestation, female rats were assigned to receive either water (control group) or a 20% fructose solution (fructose-fed group). Water or fructose solution were administered to dams from day 1 of gestation to postnatal day 21. Immediately after weaning, hippocampi of offspring were removed for analysis of antioxidant enzyme (Sod1, Sod2, Gpx1, Gpx4, and Cat) messenger RNA transcript levels. Levels of the Cat transcript were significantly lower in the fructose-fed relative to the control group. The Cat protein level was also significantly lower in the fructose-fed relative to the control group as with the messenger RNA transcript levels. Moreover, Cat promoter DNA methylation levels were higher in the fructose-fed group. The present study indicates that maternal fructose consumption may decrease offspring hippocampal Cat transcript levels via altered DNA methylation, which may result in higher levels of oxidative stress due to a decreased ability to neutralize lipid peroxides.

Sarcopenia is a multifaceted geriatric syndrome associated with the loss of muscle mass. We examined the relationship between low muscle mass and inflammatory cytokines in the context of aging. This study involved 299 participants (127 men and 172 women; mean age 63.3 ± 9.8 years) who underwent health checkups for body composition and inflammatory cytokine (TNF-alpha, IL-6, and MCP-1) levels. Muscle mass was determined using the skeletal muscle mass index. We divided the participants into the normal (N) and low muscle mass (L) groups and compared the levels of inflammatory cytokines in nonelderly ( p < 0.05 ). However, there was no significant difference in the inflammatory cytokine levels between the groups. Among the elderly subjects, the TNF-alpha level was significantly lower in the L group than in the N group ( p < 0.05 ), whereas there were no significant differences in the IL-6 and MCP-1 levels. Moreover, TNF-alpha was identified as a risk factor for the L group in the logistic regression analysis (Exp (B) 0.935, 95% CI: 0.876–0.997, p = 0.04 ). Although a low TNF-alpha level is a risk factor for low muscle mass, inflammatory cytokine levels are not necessarily elevated in elderly individuals with the loss of muscle mass.

BackgroundDNA methylation plays an important role in the pathogenesis and progression of cardiovascular disease (CVD) but the prospective association of DNA methylation with CVD has not been evaluated. Here, we conducted a prospective study to examine whether long interspersed nuclear element-1 (LINE-1) DNA methylation is associated with CVD mortality in a Japanese population.MethodsWe targeted 822 Japanese who participated in a health check-up in 1990 and had no clinical history of cancer, stroke or ischaemic heart disease. DNA was extracted from peripheral blood mononuclear cells and LINE-1 DNA methylation at three CpG sites was measured using a pyrosequencing method. We used propensity score (PS) matching to reduce the effect of potential confounding.ResultsDuring 18 118.7 persons-years of follow-up, there were 329 deaths from all-causes and 85 deaths from CVD. In PS-matched analysis, a significantly higher HR for CVD mortality was observed in the hypermethylation group than in the hypomethylation group for elderly participants (HR 2.77; 95% CI 1.55 to 4.93). No significant association between LINE-1 DNA methylation and CVD was observed for middle-aged participants.ConclusionsBased on this prospective study, we suggest that LINE-1 DNA hypermethylation is associated with increased CVD mortality risk in an elderly population.

Background and Aims: In gastrointestinal neuroendocrine tumors (GI-NETs), tumor size and grading based on cellular proliferative ability indicate biological malignancy but not necessarily clinically efficient prognostic stratification. We analyzed tumor size- and grading-based prevalence of lymphovascular invasion in GI-NETs to establish whether these are true biological malignancy indicators. Methods: We included 155 cases (165 lesions), diagnosed histologically with GI-NETs, that had undergone endoscopic or surgical resection. Patient age, sex, method of treatment, tumor size, invasion depth, lymphovascular invasion positivity according to Ki-67 index-based neuroendocrine tumor grading, distant metastases, and outcome were evaluated. The primary endpoints were the prevalence of lymphovascular invasion according to tumor size and grading. Results: Overall, 24.8% were positive for lymphovascular invasion. There was a high rate of lymphovascular invasion positivity even among grade 1 cases (22.8%). The rate of lymphovascular invasion was 3.4% for grade 1 cases Conclusions: GI-NETs ≤10 mm had a lymphovascular invasion prevalence exceeding 10%. The lymphovascular invasion impact in GI-NET development is incompletely understood, but careful follow-up, including consideration of additional surgical resection, is crucial in cases with lymphovascular invasion.

Osteoporosis is a disease characterized by deterioration of bone tissue and mass, with an increasing global prevalence. Therefore, the discovery of biomarkers for osteoporosis would help to guide appropriate treatment. Circulating microRNAs (miRNAs) have become increasingly recognized as biomarkers for detecting diseases. However, few studies have investigated the association of circulating miRNA with osteoporosis in the general population. The aim of this study was to identify miRNA associated with osteoporosis in a general resident health check-up for potential use as an osteoporosis biomarker. We conducted a cross-sectional study as part of a health check-up program and recruited 352 volunteers (139 men, 213 women, mean age 64.1±9.6 years). Osteoporosis was diagnosed according to the WHO classification. Twenty-two candidate microRNAs were screened through real-time quantitative PCR, and miRNAs associated with osteoporosis were analyzed using logistic regression analysis including other risk factors. In total, 95 females and 30 males were diagnosed with osteoporosis with bone mineral density tests (BMD: T‐score<−2.5). We found that miR195 was significantly lower in females, while miR150 and miR222 were significantly higher in males. The results of the logistic regression analysis indicated that in females, higher age and lower miR195 (odds ratio: 0.45, 95% confidential interval: 0.03–0.98) were significant risk factors for lower BMD, while the presence of a smoking habit and lower miR150 (odds ratio: 1.35, 95% confidential interval: 1.02–1.79) were significant risk factors for osteoporosis. Serum levels of miR195 and miR150 are independently associated with low bone mineral density in females and males, respectively.

Background: MicroRNAs (miRNAs) play crucial roles in the development of various diseases, including chronic kidney disease (CKD). Although previous studies in clinically severe patients have investigated associations between CKD and miRNAs, with particular attention on renal fibrosis, relationships in a general population have yet to be established. The aim of this study was to examine the relationship between expression level of circulating miRNAs and CKD in a middle-aged Japanese population. Methods: A final total of 513 individuals (216 men and 297 women) who participated in the health check-up program in 2012 were included in our analysis. Quantitative real-time polymerase chain reaction was used to determine expression levels of 22 miRNAs. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine level, sex, and age. Participants with eGFR

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Background DNA methylation plays an important role in progression of cardiovascular disease (CVD). The methylation status of long interspersed nuclear element-1 (LINE-1) reflects the global DNA methylation level and is associated with lipid profiles and glycemia. We conducted a longitudinal study to examine the association between LINE-1 DNA methylation and CVD mortality in a Japanese elderly population. Methods We targeted for 357 subjects (143 men and 214 women) who were more than 60 years, participated in the health checkup in 1990, and had no clinical history of cancer, stroke, or ischemic heart disease. During 29 years of follow-up period, total 69 subjects were died from CVD, and died of cerebrovascular disease (CBD) and ischemic heart disease (IHD) were 25 and 13, respectively. LINE-1 DNA methylation was measured using PBMCs. We defined the hypermethylation group as greater than median of the LINE-1 DNA methylation levels and hypomethylation group as others. Multivariable Hazard ratios (HRs) for each disease mortality were calculated by the Cox proportional hazard model. We adjusted for age, sex, smoking habits, and alcohol consumption. Results Significantly higher HRs for CVD and CBD mortality were observed in the hypermethylation group compared to the hypomethylation group (CVD: HR 1.67 [95%CI 1.02-2.73], CBD: HR 3.29 [95%CI 1.29-8.40]). However, IHD mortality did not associated with LINE-1 DNA methylation. Conclusions We found that LINE-1 DNA hypermethylation in PBMCs was associated with high CVD mortality, especially CBD mortality. Key messages Higher levels of LINE-1 methylation in PBMCs can be a predictive marker for CBD risk

Background Although dementia is a huge problem in public health, no fundamental biomarker has been established to detect cognitive decline at the early stage. MicroRNAs (miRNAs) regulate gene expression, and are associated with the development of various diseases. Methods The subjects of this prospective study were 162 (75 men, 87 women) residents who attended a health examination in Yakumo town in Hokkaido, in 2012 and re-attended at least once while 2013 to 2015. Serum samples were collected in 2012 and serum miRNA were measured by qRT-PCR. We used a short version of the Mini-Mental State Examination (SMMSE) to screen cognitive function, and calculated the change in SMMSE score per year. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) of serum miRNA levels for cognitive decline (decrease of greater than 0.5 points per year) using the lowest tertile group of miRNAs as the reference by logistic regression analysis. Results The mean age and change in SMMSE score of the subjects was 63.9±9.6 years and -0.03±1.19 points. Odds ratios (ORs) for cognitive decline were significantly higher in the highest tertile of serum miR-221 (OR = 3.24, 95%CI=1.20-8.72) and miR-222 (OR = 4.01, 95%CI=1.36-11.80) even if confounding factors were adjusted. Conclusions High serum levels of miR-221 and -222 were significantly associated with cognitive decline. Key messages High serum levels of miR-221 and -222 may be potential candidate biomarkers for prediction of cognitive decline.

The ratio of human nonmercaptalbumin (HNA) and reduced albumin (HMA) may be a new marker for oxidative stress. Locomotive syndrome (LS) is reduced mobility due to impairment of locomotive organs. We investigated whether the HNA/HMA ratio could be a new biomarker of LS. This study included 306 subjects (mean age 64.24 ± 10.4 years) who underwent LS tests, grip strength, walking speed, and tests for HNA and HMA. Oxidative stress was measured by the ratio of HMA (f(HMA) = (HMA/(HMA + HNA) × 100)), and the subjects were divided into normal (N group, f[HMA] ≥ 70%) and low (L group, f[HMA] &lt, 70%) groups. There were 124 non-elderly (&lt, 65 years) and 182 elderly subjects (≥65 years). There were no significant differences in LS, grip strength, and walking speed between the L and N groups in the non-elderly subjects. However, significant differences were found in the elderly subjects. In logistic regression analysis, there was an association between f(HMA) and the LS severity at older ages. LS in the elderly is associated with a decline in HMA and, thus, an increase in oxidative stress. Thus, f(HMA) is a new biomarker of LS.

Fructose consumption is rising globally, but maternal high fructose intake might adversely affect offspring. Our previous report demonstrated that excess maternal fructose intake impairs hippocampa...

Hemodialysis patients have conditions that increase cardiac output (CO), including arteriovenous fistula, fluid retention, vasodilator use, and anemia. We sought to determine the relationships between these factors and CO and to evaluate the effects of the high-output states on ventricular morphology, function, and myocardial energetics in hemodialysis patients, using noninvasive load-insensitive indices. Cardiovascular function was assessed in hemodialysis patients with high output [ejection fraction ≥ 50%, cardiac index (CI) > 3.5 L/min/m2, n = 30], those with normal output (CI

Chronic idiopathic intestinal pseudo-obstruction (CIIP) caused by impaired intestinal peristalsis leads to intestinal obstructive symptoms. A 20-year-old man had marked esophageal dilatation that was found incidentally on chest radiography during a health examination. Chest/abdominal contrast-enhanced computed tomography and endoscopy showed marked esophageal and duodenal dilatation without mechanical obstruction. Upper gastrointestinal series and high-resolution esophageal manometry revealed absent peristalsis in the dilated part. CIIP was suspected in the patient's father, suggesting familial CIIP. The patient likely had signs of pre-onset CIIP. This is the first case of suspected CIIP in which detailed gastrointestinal tract examinations were performed before symptoms appeared.

Objective: Thyroid hormones have various effects on cardiac and circulatory systems, leading to arrhythmias and heart failure. In Europe and the United States, it has been reported that elevated thyroid hormones within the normal range have been reported to be associated with a risk of atrial fibrillation, however, there was no report on Japanese cases, a country that differs in iodine intake and ethnicity from the West. Therefore, we evaluated the abnormality of thyroid function in a large number of cases of atrial fibrillation (AF) who received catheter ablation (RFCA) in Japan. Methods: We evaluated 2,937 cases of atrial fibrillation (2,084 males, mean age 64.1±10.7 years and 853 females, 69.0±8.5 years) who underwent RFCA at the Gunma Prefectural Cardiovascular Center between 2012 and 2018. As a control we used a total of 15,660 participants for health check-up (9,176 males, mean age 49.7±9.8 years and 6,484 females, 48.9±10.3 years) from 2006 to 2013, and we evaluated thyroid function after adjusting for gender-specific age. Results: The prevalence of overt hyperthyroidism was significantly higher in the RFCA-treated male group (0.43%) than in the control group (0.07%), even after adjusting for age (p

OBJECTIVES: Nonalcohol fatty liver disease (NAFLD) is one of the considerable health problems in the world. NAFLD is a representative phenotype in the liver reflecting individual's lifestyle. Previous studies suggested that a single nucleotide polymorphism (SNP) in the CD36 gene was associated with dietary fat intake and fat metabolism. Therefore, we hypothesized that this SNP may be associated with fatty liver (FL) and NAFLD. We conducted this cross-sectional study to examine the association between two CD36 polymorphisms (rs1761667 and rs1527483) and FL and NAFLD in a Japanese population. METHODS: A total of 525 local residents participated in the health check-up in Yakumo town, Hokkaido, Japan. This cross-sectional study was conducted based on clinical information collected in this health check-up. Among all participants, 57 people were excluded due to the inadequate informed consent, clinical history of liver disease. Genotyping of two polymorphisms in the CD36 gpgbrkkene was performed by using the PCR-CTPP method. Ultrasound examination was performed by four qualified ultrasonographers. In this present, NAFLD was defined as 1) presence of FL and 2) a daily alcohol consumption

Objectives A diet rich in fish and ω-3 polyunsaturated fatty acids (PUFAs) has been thought to reduce the risk for cardiovascular disease (CVD). The beneficial effects of fish oil and ω-3 PUFA on CVD can be mediated by epigenetic status of the genes associated with lipid metabolism and inflammation. The aim of this study was to investigate whether dietary fish and fatty acid (FA) intakes are associated with leukocyte ATP-binding cassette transporter A1 (ABCA1) DNA methylation levels in a Japanese population. Methods This cross-sectional study included 298 adults (137 men and 161 women) without clinical history of CVD or cancer. The pyrosequencing method was used to measure leukocyte ABCA1 DNA methylation levels. Dietary fish and FA intakes were assessed based on the validated food frequency questionnaire. Results Mean ABCA1 DNA methylation levels were significantly lower in the highest fish intake groups (≥5–6/wk) compared with the lowest intake group (≤1–2/wk; P = 0.004). In multivariable linear regression analyses, higher dietary intake of ω-3 PUFAs and ω-3 highly unsaturated fatty acids was significantly associated with decreased levels of ABCA1 DNA methylation (P = 0.001 and 0.005); whereas no significant associations were seen between intake of dietary saturated fatty acid, monounsaturated fatty acid, and ω-6 PUFAs and ABCA1 DNA methylation. Conclusion Higher dietary fish and ω-3 PUFA intake were associated with lower ABCA1 DNA levels in a Japanese population. The present results may bring potential insights on biological mechanisms underlying the protective effects of dietary fish and ω-3 PUFA intakes on CVD.

Thioredoxin-interacting protein (TXNIP) inhibits the activity of thioredoxin (TXN), leading to increased oxidative stress. Expression of the TXNIP gene is regulated by DNA methylation. However, no study has reported the influence of lifestyle factors on TXNIP DNA methylation. Our goal was to determine the association between smoking habits and TXNIP DNA methylation levels in a Japanese population. We conducted a cross-sectional study of 417 subjects (180 males and 237 females) participating in a health examination. We used a pyrosequencing assay to determine TXNIP DNA methylation levels in leukocytes. The mean TXNIP DNA methylation level in current smokers (75.3%) was significantly lower than that in never and ex-smokers (never: 78.1%, p < 0.001; ex: 76.9%, p = 0.013). Multivariable logistic regression analyses showed that the OR for TXNIP DNA hypomethylation was significantly higher in current smokers than that in never smokers, and significantly higher in current smokers with years of smoking ≥ 35 and Brinkman Index ≥ 600 compared to that in non-smokers. In conclusion, we found that current smokers had TXNIP DNA hypomethylation compared to never and ex-smokers. Moreover, long-term smoking and high smoking exposure also were associated with TXNIP DNA hypomethylation.

Background A recent study has reported that incidence of chronic kidney disease (CKD) is higher in evacuees, but the molecular mechanism still remains unclear. One plausible hypothesis is a change in vascular function following to psychological distress. In order to assess molecular mechanisms underlying this association, we examined whether cardiovascular disease (CVD)-associated miRNAs (miR-126, miR-197, and miR-223) were associated with CKD among Japanese elderly survivors after an earthquake. Methods We analyzed 1385 individuals (670 men and 715 women) who participated in a post-disaster health check-up after the Great East Japan Earthquake, which occurred in 2011. The check-up involved collection of information about lifestyle, clinical history, the degree of housing damage, and baseline measurement of the estimated glomerular filtration rate. Expression levels of miRNAs were determined using real-time polymerase chain reaction. Estimated glomerular filtration rate (eGFR) was calculated using sex, age, and serum creatinine. CKD was defined as eGFR 2. The multivariable regression analyses were performed to examine the associations between CVD-associated miRNAs and CKD after adjusting potential confounders. Results Mean age (standard deviation) of participants with normal kidney function and CKD was 62.7 (10.6) and 71.9 (8.1) years, respectively. Expression levels of these miRNAs in participants with CKD were significantly lower than normal kidney function (all p p = 0.04). Conclusions This cross-sectional study suggested that CVD-associated miRNAs were an important factor of CKD in an elderly Japanese population after earthquake. Future studies need to examine this association in longitudinal dataset.

Aims Recent increases in fructose consumption have raised concerns regarding the potential adverse intergenerational effects, as maternal fructose intake may induce physiological dysfunction in offspring. However, no reports are available regarding the effect of excess maternal fructose on reproductive tissues such as the ovary. Notably, the maternal intrauterine environment has been demonstrated to affect ovarian development in the subsequent generation. Given the fructose is transferred to the fetus, excess fructose consumption may affect offspring ovarian development. As ovarian development and its function is maintained by 17β-estradiol, we therefore investigated whether excess maternal fructose intake influences offspring ovarian estradiol synthesis. Rats received a 20% fructose solution during gestation and lactation. After weaning, offspring ovaries were isolated. Key findings Offspring from fructose-fed dams showed reduced StAR and P450(17α) mRNA levels, along with decreased protein expression levels. Conversely, attenuated P450arom protein level was found in the absence of mRNA expression alteration. Consistent with these phenomena, decreased circulating levels of estradiol were observed. Furthermore, estrogen receptor α (ERα) protein levels were also down-regulated. In accordance, the mRNA for progesterone receptor, a transcriptional target of ERα, was decreased. These results suggest that maternal fructose might alter ovarian physiology in the subsequent generation.

INTRODUCTION Previous studies have demonstrated an association between low serum creatinine levels and adverse outcomes in patients undergoing maintenance hemodialysis. However, little is known regarding whether long-term changes in serum creatinine predict outcomes independently and incrementally over a single point evaluation. METHODS Serum creatinine data at index (June 2013) and for the 18 months prior to the index blood sampling (between January 2012 and June 2013) were evaluated in 346 hemodialysis patients. Patients were followed from the index blood sampling for primary (all-cause mortality) and secondary (cardiovascular death) endpoints. FINDINGS During a median follow-up of 5.7 years, there were 82 all-cause and 25 cardiovascular deaths. Compared to patients who survived, those who died displayed a greater time-dependent reduction in creatinine levels during the 18 months prior to the index assessment, coupled with a greater decrease in predialysis body weight (interaction p = 0.007). Patients who displayed creatinine decline over the prior 18 months (∆ creatinine

Background Higher intake of fruits and vegetables is associated with reduced risk of specific types of cancer and of cardiovascular disease (CVD), but the protective role of the vitamins contained in fruits and vegetables on CVD is controversial. This discrepancy can raise the question of the effects of antioxidants in vitamins on CVD. Recently, we reported that higher vegetable intake was significantly associated with the decreased DNA methylation level of ATP-binding cassette transporter A1 (ABCA1), a gene associated with HDL-cholesterol metabolism. Objective We investigated whether ABCA1 DNA methylation mediates an effect of dietary vitamin intake on lipid profiles, an important risk factor for CVD, in a Japanese population. Methods A total of 225 individuals (108 men and 117 women) with no clinical history and no drug use for dyslipidemia participated in this cross-sectional study. We used the pyrosequencing method to measure the ABCA1 DNA methylation levels at 8 CpG sites, and we used mean DNA methylation level in statistical analysis. Dietary vitamin intake was assessed with the FFQ and adjusted for the residual method. Results In women, higher dietary vitamin intake [vitamin A, β-carotene, folic acid, vitamin C (VC), vitamin D, and vitamin E] was significantly associated with lower mean ABCA1 DNA methylation levels (P = 0.004, 0.03, 0.005, 0.001, 0.03, and 0.04, respectively). In addition, in women, we found a significant inverse association between mean ABCA1 DNA methylation and HDL cholesterol (P = 0.04) but not for other lipid indexes. Mediation analysis showed a significant indirect effect of VC intake on HDL cholesterol through ABCA1 DNA methylation level in women (P = 0.04). Conclusions Although this study does not prove causality, the results suggest that ABCA1 DNA methylation mediates the protective effect of VC on HDL cholesterol in women, which could offer a novel biological mechanism in CVD prevention.

Dietary intake of vegetables is one of the key lifestyle factors associated with preventing cancer and cardiovascular disease (CVD). Although previous studies have provided evidence that dietary factors can alter global DNA methylation levels in humans, little work has been done on dietary factors influencing methylation levels of specific genes associated with CVD. The aim of this study was to examine whether dietary intake of vegetables was associated with adenosine triphosphate-binding membrane cassette transporter A1 (ABCA1) DNA methylation levels in leukocytes in a Japanese population.This cross-sectional study included 279 Japanese adults (125 men, 154 women) without any clinical history of cancer, stroke, or ischemic heart disease. ABCA1 DNA methylation levels in leukocytes were measured using a pyrosequencing method. Information on dietary vegetable intake was obtained from the validated food frequency questionnaire.Mean ABCA1 DNA methylation levels in men and women were 35.6% ± 6.5% and 36.9% ± 6.7%, respectively. In women, multivariable linear regression analysis showed that the group with the highest dietary vegetable intake (carrot, broccoli, pumpkin, and all vegetables) showed significantly lower levels of ABCA1 DNA methylation than the lowest intake group (P = 0.04,0.001, 0.001, and 0.02, respectively). No significant association was observed between dietary intake of vegetables and DNA methylation levels in men.High dietary intake of vegetables was associated with decreased ABCA1 DNA methylation levels in Japanese women. This may contribute to a better understanding of the protective effects of dietary vegetable intake on CVD.

Global fructose consumption is on the rise; however, maternal high-fructose intake may have adverse effects on offspring. We previously demonstrated that excessive fructose intake by rat dams altered steroidogenic gene transcription in the hippocampus of offspring. Herein, we examined how maternal high-fructose intake influences the regulation of adrenal glucocorticoid levels in offspring. Rat dams received 20% fructose solution during gestation and lactation. After weaning, the offspring were provided normal water. Maternal high-fructose intake did not alter mRNA expression levels of adrenal corticosterone-synthesizing and corticosterone-inactivating proteins or the circulating adrenocorticotropic hormone levels of offspring at postnatal day (PD) 21; however, it increased circulating corticosterone levels and decreased mRNA and protein levels of adrenal 5α-reductase type 1 and 11β-hydroxysteroid dehydrogenase type 2 in offspring at PD160. Furthermore, maternal high-fructose intake enhanced DNA methylation of the adrenal 5α-reductase 1 promoter region in PD160 offspring. Thus, maternal high-fructose intake was found to affect adrenal steroid hormone clearance in adult offspring - at least in part - through epigenetic mechanisms.

Background End-stage renal disease is a major clinical and public health problem, and cardiovascular disease accounts for half of the mortality in hemodialysis patients. An existing mortality risk score (AROii score) or N-terminal pro–brain natriuretic peptide (NT-proBNP) level have modest predictive power, but there is room for improvement. There are emerging cardiac biomarkers (soluble isoforms of ST2 [sST2], galectin-3 [Gal-3]), and uremic toxicity (indoxyl sulfate). We sought to determine whether these biomarkers predict cardiovascular outcomes in hemodialysis patients and have incremental prognostic value over the clinical score and NT-proBNP level. Methods A total of 423 hemodialysis patients were prospectively followed up for primary (all-cause death) and secondary end points (a composite of all-cause death or cerebrocardiovascular events). Results During a mean follow-up of 2.1 ± 0.4 years, there were 48 all-cause deaths and 78 composite outcomes. Soluble isoforms of ST2, Gal-3, and NT-proBNP were associated with all-cause deaths but indoxyl sulfate was not in both log-rank test and receiver operating characteristic analysis. Both sST2 and Gal-3 had independent and incremental prognostic value for both outcomes over the AROii score and NT-proBNP. Although adding sST2 did not reclassify over the model-based AROii score and NT-proBNP for all-cause death, further addition of Gal-3 did. Subgroup analyses of patients with left ventricular ejection fraction measurement (n = 301) corroborated these results, where the 2 biomarkers remained independent and incremental for both all-cause death and composite outcome after adjusting for the risk score and the ejection fraction. Conclusions Both sST2 and Gal-3 had independent and incremental prognostic values over NT-proBNP and an established risk score in patients with hemodialysis. Assessment of sST2 and Gal-3 further enhances risk stratification.

Aims Fructose may play a crucial role in the pathogenesis of metabolic syndrome (MetS). However, the pathogenic mechanism of the fructose-induced MetS has not yet been investigated fully. Recently, several reports have investigated the association between mitochondrial DNA (mtDNA) and MetS. We examined the effect of fructose-rich diets on mtDNA content, transcription, and epigenetic changes. Main methods Four-week-old male Sprague-Dawley rats were offered a 20% fructose solution for 14 weeks. We quantified mRNAs for hepatic mitochondrial genes and analyzed the mtDNA methylation (5-mC and 5-hmC) levels using ELISA kits. Key findings Histological analysis revealed non-alcoholic fatty liver disease (NAFLD) in fructose-fed rats. Hepatic mtDNA content and transcription were higher in fructose-fed rats than in the control group. Global hypomethylation of mtDNA was also observed in fructose-fed rats. Significance We showed that fructose consumption stimulates hepatic mtDNA-encoded gene expression. This phenomenon might be due to epigenetic changes in mtDNA. Fructose-induced mitochondrial epigenetic changes appear to be a novel mechanism underlying the pathology of MetS and NAFLD.

The article “Mesalazine formulation intolerance due to suspected excipient allergy in the treatment of ulcerative colitis: a case report”, written by Yoshinori Arai, Maiko Ogawa, Fumitsugu Yamane, Natsuki Sumiyoshi, Rikako Arimoto.

Maternal fructose consumption affects the metabolic functions of offspring later in life. However, the molecular mechanism remains poorly understood. Differences of microRNA expression profile and DNA methylation status are a candidate mechanism to explain the developmental programming that contributes to the development of a metabolic disorder. This study examined the transgenerational effect of maternal fructose consumption from the perspective of epigenetic modification. To do this, we collected serum and liver tissues from male offspring rats that were exposed to maternal distilled water or 20% fructose water during gestation and lactation. A decreased serum high-density lipoprotein cholesterol (HDL-C) level was observed in the offspring of fructose-fed dams at postnatal day (PD) 160. Given research indicating a role of liver X receptor alpha (LXRA) in cholesterol metabolism, we analyzed Lxra expression. Real-time polymerase chain reaction analysis demonstrated that offspring that were delivered from fructose-fed dams exhibited decreased Lxra gene expression in their liver tissue. There is a well-established association between Lxra expression and the level of DNA methylation and miR-206 expression. Pyrosequencing assays revealed no differences in the level of DNA methylation in the Lxra promoter region, whereas miR-206 expression was increased in the liver at PD 60 and 160. Our data indicate that early-life exposure to maternal fructose results in changing of miR-206 expression level in the liver that suppresses the expression of Lxra. This phenomenon may be associated with the decreased serum HDL-C level in offspring.

Indoxyl sulfate (IS), a uremic toxin, has been reported to have hypertrophic effects on the heart. Previous studies, however, have shown no association between elevated IS levels and cardiovascular outcomes in hemodialysis patients. We hypothesized that, despite left ventricular (LV) hypertrophy, myocardial contractility and ventricular–arterial coupling would remain preserved, and that this would explain the reason for the absence of prognostic impact of IS. We evaluated the association of IS with LV structure, contractility, vascular function, and mechanical efficiency (ventricular–arterial coupling and stroke work/pressure volume area) in 154 patients on hemodialysis, using echocardiography-based pressure–volume loop assessment. As expected, subjects in the high IS group (IS ≥ 33.8 μg/mL) had greater LV mass index and end-diastolic volume index compared to subjects in the low IS group (IS

Background Cardiovascular disease is the leading cause of morbidity and mortality in patients receiving hemodialysis. Systemic metabolic perturbation is one of the hallmark abnormalities in patients at high cardiovascular risk. We sought to determine the relationship between circulating ketone body and clinical outcomes in patients with prevalent hemodialysis. Methods and Results We retrospectively assessed the relationship between serum β‐hydroxybutyrate (β OHB ), the most abundant ketone body in the circulation, and prognosis in 405 stable hemodialysis patients. During a mean follow‐up of 3.2±0.9 years, there were 54 major adverse cardiovascular events (defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization attributed to heart failure) and 67 all‐cause deaths. Major adverse cardiovascular events rates increased from 11.1 per 1000 person‐years in the lowest β OHB quintile (409 μmol/L). After adjusting for demographic characteristics, coronary artery disease, and atrial fibrillation, the highest β OHB quintile was associated with increased risk of major adverse cardiovascular events compared with the lowest quintile (hazard ratio, 10.2; 95% confidence interval [3.35–44.0]; P OHB were independently and incrementally associated with major adverse cardiovascular events over the model based on an established risk score (the second Analyzing Data, Recognizing Excellence and Optimizing Outcomes cohort score) and N‐terminal pro‐B‐type natriuretic peptide (chi square 39.9 versus 21.7; P OHB and all‐cause death. Conclusions Increased serum β OHB levels were independently associated with cardiovascular events and all‐cause death in patients receiving hemodialysis. These results highlight the need for future studies to understand the mechanisms underlying these observations.

\n Discretization errors due to the digitization of computed tomography images and the calculation grid are a significant issue in radiation therapy. Such errors have been quantitatively reported for a fixed multifield intensity-modulated radiation therapy using traditional linear accelerators. The aim of this study is to quantify the influence of the calculation grid size on the dose distribution in TomoTherapy. This study used ten treatment plans for prostate cancer. The final dose calculation was performed with “fine” (2.73 mm) and “normal” (5.46 mm) grid sizes. The dose distributions were compared from different points of view: the dose-volume histogram (DVH) parameters for planning target volume (PTV) and organ at risk (OAR), the various indices, and dose differences. The DVH parameters were used Dmax, D2%, D2cc, Dmean, D95%, D98%, and Dmin for PTV and Dmax, D2%, and D2cc for OARs. The various indices used were homogeneity index and equivalent uniform dose for plan evaluation. Almost all of DVH parameters for the “fine” calculations tended to be higher than those for the “normal” calculations. The largest difference of DVH parameters for PTV was Dmax and that for OARs was rectal D2cc. The mean difference of Dmax was 3.5%, and the rectal D2cc was increased up to 6% at the maximum and 2.9% on average. The mean difference of D95% for PTV was the smallest among the differences of the other DVH parameters. For each index, whether there was a significant difference between the two grid sizes was determined through a paired t-test. There were significant differences for most of the indices. The dose difference between the “fine” and “normal” calculations was evaluated. Some points around high-dose regions had differences exceeding 5% of the prescription dose. The influence of the calculation grid size in TomoTherapy is smaller than traditional linear accelerators. However, there was a significant difference. We recommend calculating the final dose using the “fine” grid size.

Background Circulating microRNAs (miRs) may be promising biomarkers for several diseases. We previously found that miR-122 can function as a biomarker for non-alcoholic fatty liver disease (NAFLD). However, little is known regarding the time course of circulating miR-122 levels during the development of NAFLD. Here, we examined circulating miR-122 levels using a rat model of NAFLD. Methods To clarify changes in serum levels of miR-122 during development of NAFLD, experimental rats were fed a high-fat diet (HFD) for 2–10 weeks, while control rats received standard chow. Serum and liver tissue was collected from all animals at 2, 6, and 10 weeks of feeding. Clinical laboratory parameters (cholesterol, TG, AST, ALT, NEFA) were determined by biochemistry analyzer. Hepatic lipid accumulation was estimated by Oil red O staining. Circulating miR-122 levels were then measured by real-time polymerase chain reaction. Results Over the 10 weeks of feeding, body weight, total liver lipids, and liver and serum triacylglycerol were increased in the HFD group compared to the control group. However, no significant changes in serum alanine aminotransferase activity were observed, suggesting that NAFLD status was mild. In contrast, we observed drastic up-regulation of circulating miR-122 levels. Our findings suggest that serum miR-122 level is indeed useful for assessing early NAFLD and might be superior to clinical markers traditionally used to monitor hepatic disease.

Hippocampal functions such as neuronal protection and synapse formation are positively modulated by neurosteroids, which are synthesized de novo within the brain. However, the mechanisms regulating neurosteroidogenesis remain unclear. Fructose, which is used as a sweetener, affects steroid hormone synthesis in peripheral endocrine organs. This monosaccharide can penetrate the blood-brain barrier and impair hippocampal function. Also, fructose is secreted into milk and is thus delivered to the fetus. Based on these observations, we hypothesized that the hippocampal neurosteroidogenesis in the offspring may be affected by maternal fructose consumption. Female rats were fed with normal water or 20% fructose solution during gestation and lactation. Maternal calorie intake did not change significantly, and no significant change in body weight was observed. The levels of messenger RNAs (mRNAs) for steroidogenic enzymes and proteins in the hippocampus of the offspring were analyzed by real-time reverse transcriptase polymerase chain reaction. Maternal fructose consumption during gestation and lactation increased mRNA levels of P450(11β)-2, 11β-HSD-2, and 17β-HSD-1 in the offspring hippocampus, and reduced levels of mRNAs for StAR, PBR, and 17β-HSD-3. Maternal fructose consumption might influence hippocampal neurosteroidogenesis in offspring.

Chronic kidney disease (CKD) patients are prone to disturbances in the intestinal microbiota, which contributes to CKD progression and complications. We previously reported a reduction of serum phosphorus (P) levels in hemodialysis patients receiving oral encapsulated bifidobacteria. The present study was conducted to clarify the mechanisms of P-lowering effect of bifidobacteria on CKD rats. CKD was induced in rats by 5/6 nephrectomy. Five weeks later, the rats were fed for 4 weeks on a powder diet containing encapsulated bifidobacteria. At the end of the study, intestinal contents were sampled for analyses of pH, intestinal flora and short-chain fatty acids (SCFAs). Oral administration of bifidobacteria halted the onset and progression of hyperphosphatemia in CKD rats. The increased number of bifidobacteria was confirmed in the cecum. In addition, the increase in intestinal pH in CKD rats was decreased after bifidobacteria treatment, along with increases in some SCFAs. Furthermore, positive correlation between serum P levels and intestinal pH was observed. In conclusion, the mechanism for the P-lowering effect of bifidobacteria was supposed as follows: CKD conditions increase aerobic bacteria which hydrolyze urea into ammonia. Elevated pH decreases ionization of intestinal calcium (Ca) which leads to an increase in free phosphate ions through reduction of Ca phosphate crystal precipitation. Administered bifidobacteria fermented carbohydrates to produce SCFAs, resulting in acidification of the intestinal lumen. The resulting low intestinal pH increases Ca ionization, which binds with free phosphate ions as an intrinsic P binder, resulting in the reduction of serum P levels.

Purpose It has been demonstrated that circulating microRNA profiles are affected by physiological conditions. Several studies have demonstrated that microRNAs play important roles in the regulation of adiposity. However, few have investigated the relationship between circulating microRNAs and obesity, which has become a major public health problem worldwide. This study investigated the association between circulating microRNAs and obesity in a Japanese population. Methods Obesity parameters, such as subcutaneous and visceral fat adipose tissue, body fat percentage, and body mass index were assessed in a cross-sectional sample of 526 participants who attended health examinations in Yakumo, Japan. In addition, five circulating microRNAs (miR-20a, -21, -27a, -103a, and -320), which are involved in adipocyte proliferation and differentiation, were quantified using real-time polymerase chain reaction amplification. Results We compared the circulating microRNA concentrations in a percentile greater than 75th (high) with below the value (low) of subcutaneous adipose tissue, visceral fat adipose tissue, body mass index, and per cent body fat. For visceral fat adipose tissue, significant decrease in miR-320 expression was observed in high group. Also, for body mass index, significant change of miR-20a, -27a, 103a, and 320 expression level was observed in high group. Multiple linear regression analysis demonstrated that circulating levels of some microRNA such as miR-27a were significantly associated with subcutaneous adipose tissue, visceral fat adipose tissue, and body mass index. Conclusions Our findings support the need for further studies to determine whether such changes are consistent across different populations and whether the identified microRNAs may represent novel biomarkers to predict the susceptibility and progression of obesity-related disorders.

Background In many industrialized countries, non-alcoholic fatty liver disease (NAFLD) is recognized as an important disease that increases the risk of cardiovascular disease, type-2 diabetes, and metabolic syndrome. Most people with NAFLD are asymptomatic, and the disease is discovered incidentally during clinical laboratory tests. Present screening methods for NAFLD use ultrasound, and CT scans that are time-consuming, and a simple screening method for NAFLD is needed. In this study, we investigated whether serum miRNAs are associated with NAFLD and assessed the potential of serum miRNAs as a biomarker for NAFLD. Methods We assessed intrahepatic fat by ultrasound scan, and the serum levels of five miRNAs (miR-21, miR-34a, miR-122, miR-145, and miR-451), which help regulate cholesterol and fatty acid homeostasis in liver tissue, by real-time PCR in a cross-sectional sample of 403 participants who attended health examinations. Results Serum levels of miRNAs, miR-21, miR-34a, miR-122, and miR-451 were higher in participants with NAFLD. The serum level of miR-122 was correlated with the severity of liver steatosis. Conclusion Serum levels of miRNAs, particularly miR-122, may be a useful biomarker for NAFLD.

Background The association of plasma cardiovascular risk markers and metabolic syndrome (MetS) with non-alcoholic fatty liver disease (NAFLD) has not been well defined. Methods Japanese men ( n = 809) had standard anthropometric measurements done, and had their liver fat quantitated by ultrasound. Three groups were identified: (1) normal controls without significant disease, (2) preliminary-metabolic syndrome (pre-MetS) cases and (3) MetS cases. Plasma adiponectin, high sensitivity-C reactive protein (hs-CRP), HOMA-IR, lipids, lipoproteins and liver enzymes were evaluated among the three groups. Results The prevalence of fatty liver was 13% in controls, 39% in pre-MetS and 62% in MetS. Plasma adiponectin and high density lipoprotein cholesterol (HDL-C) were significantly decreased, and HOMA-IR, hs-CRP, TG, remnant lipoproteins (RLPs) and small dense-LDL-C (sd LDL-C) were significantly increased in subjects with fatty liver compared to those without fatty liver. Multivariate analyses of serum parameters associated with fatty liver revealed that adiponectin and hs-CRP were more strongly associated with the presence of fatty liver than waist circumference. However, HOMA-IR, HDL-C, TG, RLP-C, RLP-TG and sd LDL-C were more strongly associated with waist circumference than with fatty liver. Factor analysis revealed that adiponectin and HDL-C were linked to liver enzymes, lipoproteins and HOMA-IR associated with fatty liver, but not with waist circumference. Conclusions Adiponectin was found to be a more specific diagnostic marker for the presence of fatty liver regardless of MetS status, and was inversely correlated with liver enzyme concentrations. However, RLPs were found to be more specifically associated with the presence of MetS.

Background Left ventricular ejection fraction (LVEF) is a predictor of adverse outcomes in hemodialysis patients. LVEF is, however, an integral parameter determined by contractility, loading condition, and coupling. We sought to determine whether these components would better predict adverse outcomes and have incremental prognostic value over a validated clinical score and EF. Methods Two hundred thirty-four hemodialysis patients were prospectively followed up for primary composite endpoint: all-cause death, nonfatal myocardial infarction, and hospitalization due to worsening heart failure (HF). Load-independent contractility (end-systolic elastance [Ees] and preload recruitable stroke work [PRSW]) and arterial afterload (arterial elastance [Ea]) were noninvasively estimated. Ventricular-arterial coupling was assessed using the Ea/Ees ratio. LV global longitudinal strain (GLS) and mitral E-wave over annular velocity E′ ratio (E/E′) were also measured. Results During a median follow-up of 776 days, 30 patients developed the primary endpoint. Ees, PRSW, GLS, S′, Ea/Ees, E/E′, and EF were independently associated with the outcome after adjusting for the clinical score and prior HF hospitalization, whereas end-diastolic volume index or arterial afterload parameters were not. The nested Cox models indicated that Ea/Ees had independent and incremental predictive value over the model based on the score and either EF or E/E′. Furthermore, Ea/Ees continued to have predictive value after adjusting for GLS. The classification and regression analysis stratified event rates ranging from 4.2% to 68.8%. Conclusions LV contractility and Ea/Ees were independently associated with adverse outcome in hemodialysis patients. Ea/Ees had an incremental prognostic value over the clinical score and EF.

Neurosteroids, steroidal hormones synthesized de novo from cholesterol within the brain, stimulate hippocampal functions such as neuron protection and synapse formation. Previously, we examined the effect of maternal fructose on the transcriptional regulation of neurosteroidogenic enzymes. We found that the mRNA expression level of the steroidogenic acute regulatory protein (StAR), peripheral benzodiazepine receptor (PBR), cytochrome P450(11β), 11β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD was altered. However, we could not determine whether maternal fructose intake played a role in the gestation or lactation period because the dam rats were fed fructose solution during both periods. Thus, in this study, we analyzed the hippocampi of the offspring of dams fed fructose during the gestation or lactation period. Maternal fructose consumption during either the gestation or lactation period did not affect the mRNA levels of StAR, P450(17α), 11β-HSD-2, and 17β-HSD-1. PBR expression was down-regulated, even when rats consumed fructose during the lactation period only, while fructose consumption during gestation tended to activate the expression of P450(11β)-2. We found that maternal fructose intake during gestation and lactation differentially affected the expression of hippocampal neurosteroidogenic enzymes in the offspring.

Background Recently, several studies have shown that microRNAs are present in high-density lipoprotein, and high-density lipoprotein-microRNA may be a promising disease biomarker. We investigated the stability of high-density lipoprotein-microRNAs in different storage conditions as this is an important issue for its application to the field of clinical research. Methods microRNAs were extracted from the high-density lipoprotein fraction that was purified from the serum. miR-135 a and miR-223, which are known to be present in high-density lipoprotein, were quantified by quantitative real-time PCR. The influence of preanalytical parameters on the analysis of high-density lipoprotein-miRNAs was examined by the effect of RNase, storage conditions, and freezing and thawing. Results The concentrations of microRNA in high-density lipoprotein were not altered by RNase A treatment (0–100 U/mL). No significant change in these microRNAs was observed after storing serum at room temperature or 4℃ for 0–24 h, and there was a similar result in the cryopreservation for up to two weeks. Also, high-density lipoprotein-microRNAs were stable for, at least, up to five freeze–thaw cycles. Conclusions These results demonstrated that high-density lipoprotein-microRNAs are relatively resistant to various storage conditions. This study provides new and important information on the stability of high-density lipoprotein-microRNAs.

There is a lack of information on stiffness parameter β, an index of arterial stiffness, in hemodialysis (HD) patients. The aim of the present study was to investigate whether stiffness parameter β is predictive of the long-term mortality of chronic HD patients.We measured biochemical parameters and the stiffness parameter β of 80 patients on maintenance HD therapy and followed their course for 4 years, and we enrolled 70 of these 80 patients in the study. We divided the 70 patients into tertiles according to their stiffness parameter β values, and conducted multivariate analyses to examine the impact of the tertiles on 4-year mortality.Older age and the presence of diabetes mellitus were found to be independently associated with higher stiffness parameter β values. Fifteen patients (21.4 %) died and 16 (22.9 %) experienced a new cardiovascular event during the follow-up period. The results of a Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality in the HD patients with highest stiffness parameter β values (p = 0.0106). According to the ROC curve, the cut-off level that yielded maximal sensitivity and specificity for predicting all-cause mortality was 10.1, and the sensitivity and specificity using the cut-off value were 69.2 and 70.2 %, respectively.The results of this study suggest that stiffness parameter β is a predictor of all-cause mortality in chronic HD patients.

Postoperative hemithoracic irradiation is regarded as an important part of the curative treatment for resectable malignant pleural mesothelioma (MPM). Because the clinical target volume in postoperative MPM is irregular and surrounded by dose-limiting critical structures, intensity-modulated radiation therapy (IMRT) is thought to be suitable. However, postoperative hemithoracic IMRT remains experimental due to a high incidence of fatal pneumonitis. Therefore, a Phase I dose escalation study for hemithoracic IMRT using helical tomotherapy was planned, and the results of the first three patients are herein reported because this technique may provide benefits to such patients. For 3 patients with postoperative MPM, who were treated by extrapleural pneumonectomy (EPP), a radiation dose of 45.0 Gy in 25 fractions was given to cover 95% of the PTV. The lung V5s of the three patients were 14.3%, 10.0%, and 31.3%, respectively. The V5s of the present plans was smaller than that of the recent IMRT planning studies. The lung V20s of these patients were 2.4%, 2.2%, and 4.3%, respectively. Their MLDs were 4.3 Gy, 3.4 Gy, and 5.8 Gy, respectively. The follow-up periods of the patients were 26, 14 and 9 months from initiation of IMRT, respectively. All patients were alive, although local and contralateral recurrences had developed in 1 patient. Only 1 patient had Grade 2 acute esophagitis and nausea. There was no treatment-related pneumonitis. Hemithoracic IMRT using helical tomotherapy may play a crucial role in adjuvant treatment for MPM after EPP.

DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status.

Vascular calcification is associated with cardiovascular disease in hemodialysis (HD) patients. Some reports have previously shown that simple assessment of aortic calcification using plain radiography is associated with cardiovascular (CV) events; however, these studies simply assessed whether aortic calcification was present or absent only, without considering its extent. Here, we evaluated the validity of grading aortic arch calcification (AoAC) to predict new CV events. We retrospectively reviewed chest X-rays in 212 asymptomatic HD patients who underwent measurement of pulse wave velocity (PWV) in 2006 without a past history of CV events. The extent of AoAC was divided into four grades (0-3). Among these subjects, the follow-up of CV events in 197 patients was completed. At baseline, AoAC grade was positively associated with age, dialysis vintage, PWV and parathyroid hormone levels, and negatively correlated with body weight and body mass index. Arterial stiffness, as determined by PWV, was also correlated with increasing AoAC grade. Eighty-nine CV events in total occurred during a mean follow-up period of 69 ± 45 months. With multivariate adjustment, Kaplan-Meier analysis showed that the incidence was significantly higher in patients with higher AoAC grade (grades 2 and 3) than in those with grade 0 or 1 (p = 0.013, log-rank test). Multivariate Cox proportional hazards analyses showed the predictive values of AoAC grade were significant (hazard ratio 1.512; p = 0.0351). AoAC detectable on chest X-ray is a strong independent predictor of CV events in accordance with PWV. Risk stratification by assessment of AoAC may provide important information for management of atherosclerotic disease in HD patients.

Aim: Vascular calcification is a cause of cardiovascular death in hemodialysis (HD) patients. The aim of the present study was to evaluate the relationship between the progression of aortic arch calcification (AoAC) and serum fibroblast growth factor (FGF)-23.Methods: The enrolled study subjects were 127 (83 men and 44 women) HD patients. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiology. Change in AoACS (ΔAoACS) was obtained by subtracting the baseline AoACS value from the follow-up AoACS value. The second assessment was performed from 5 years after the first determination.Results: The percentage of male gender in non-progressors (58.5%) was lesser than in regressors (60.0%) and progressors (74.6%). In addition, the dialysis duration in regressors (14.1±5.1 years) was shorter than in non-progressors (19.5±7.0 years) and progressors (16.8±7.5 years). Interestingly, the serum FGF-23 level in regressors (39225.5±9247.9 pg/mL) was significantly higher than in non-progressors (12896.5±26323.5 pg/mL) and progressors (14062.4±18456.8 pg/mL). Multi-ple regression analyses showed male gender (β value=0.969, F=5.092, p=0.0192), serum levels of albumin (β value=−1.395, F=4.541, p=0.0296) and log FGF-23 (β value=−0.001, F=7.273, p=0.0115) to be significant independent determinants of ΔAoACS.Conclusion: Changes in AoAC evaluated by using a simple chest radiograph are associated with serum FGF-23 levels. Excess accumulation of FGF-23 in serum may enable to inhibit the calcification process in vessel walls in chronic HD patients.

The role of decreased active vitamin D levels on vascular calcification has not been elucidated in hemodialysis (HD) patients. The aim of the present study was to evaluate the relationship between progression of aortic arch calcification (AoAC) and prescribed dose of 1alpha-hydroxy vitamin D. The enrolled study subjects were 65 (40 men and 25 women) HD patients. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiology. Change in AoACS (DeltaAoACS) was obtained by subtracting the baseline AoACS value from the follow-up AoACS value. The second assessment was performed from 2 years after the first determination. The nonprogressors (63.2 +/- 14.5 years) were significantly younger than the progressors (68.2 +/- 10.8 years) (P = 0.0419). In addition, prescribed dose of 1alpha-hydroxy vitamin D3 was significantly higher in the nonprogressors (125.5 +/- 109.1 microg) than progressors (84.8 +/- 81.1 microg) (P = 0.0371). Multiple regression analysis revealed prescribed dose of 1alpha-hydroxy vitamin D(3) (beta value = -0.324, P = 0.0051) as well as DBP (beta value = -0.418, P = 0.007), serum levels of P (beta value = 0.333, P = 0.006) and C-reactive protein (beta value = 0.237, P = 0.0048) to be significant independent determinants of DeltaAoACS. In conclusion, the evaluation of AoACS on chest radiography is a very simple tool in HD patients. Active vitamin D therapy seems to protect patients from developing vascular calcification.

Vascular calcification is associated with a poor prognosis in dialysis patients. It can be assessed with computed tomography but simple inoffice techniques may provide useful information. We compared the results obtained with a simple noninvasive technique with those obtained using multidetector computed tomography for aortic arch calcification volume (AoACV) in chronic hemodialysis (HD) patients. The enrolled study subjects were 63 (32 men and 31 women) maintenance HD patients. Calcification of the aortic arch was semiquantitatively estimated with a AoAC score (AoACS) on plain chest radiology. The AoACV was increased, with a mean value of 6.6 ranging from 0% to 36.5%. The coefficient of intraobserver variation was less than 2.5%. Aortic arch calcification score was highly correlated with AoACV (r=0.635, P