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A higher incidence of bilateral primary aldosteronism in women is reported. Treatment of bilateral primary aldosteronism usually involves mineralocorticoid receptor antagonists. However, the impact of sex on renal outcomes is unknown. We compared renal outcomes between the sexes after mineralocorticoid receptor antagonist initiation by analyzing data obtained from 415 female and 313 male patients with bilateral primary aldosteronism who were treated with spironolactone or eplerenone in the JPAS (Japan Primary Aldosteronism Study). Over the course of 5 years, the temporal reduction in the estimated glomerular filtration rate was greater in women than in men ( P 2 per year versus −1.04 mL/min per 1.73 m 2 per year, P

Objectives We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design Multicenter retrospective study by Japan PA study. Method We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI n = 15); and basal LI ≥2 with ACTH-stimulated LI n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

Objective Several clinical studies have reported that renal impairments are sometimes observed in patients with primary aldosteronism (PA). We analyzed the prevalence of renal impairments in PA patients and identified parameters that increase the risk for them. Design This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan PA study (JPAS). Data were also collected from patients with essential hypertension (EHT). Methods We compared the prevalences of proteinuria and lowered estimated glomerular filtration rate (eGFR) between patients with PA and age, sex, blood pressure and duration of hypertension-matched patients with EHT. We also performed logistic regression analysis to identify parameters that increase the risk for these renal impairments. Results Among 2366 PA patients, the prevalences of proteinuria and lowered eGFR were 10.3 and 11.6%, respectively. The prevalence of proteinuria was significantly higher in PA patients than matched-EHT patients (16.8 vs 4.4%), whereas there was no significant difference in the prevalence of lowered eGFR (17.2 vs 15.0%). The logistic regression analysis also showed that the plasma aldosterone concentration (PAC) significantly increases the risk of proteinuria and lowered eGFR, independent of other known risk factors. Conclusion Plasma aldosterone levels are closely associated with renal impairment in patients with PA. This is contrast to our earlier finding that the PAC was not itself linearly associated with cardiovascular events such as stroke or ischemic heart disease. The mechanism underlying the kidney damage in patients with PA may differ from that affecting the cardiovascular system.

Primary aldosteronism causes renal structural damage after glomerular hyperfiltration, and primary aldosteronism-specific treatment leads to an acute fall in estimated glomerular filtration rate (eGFR). We investigated whether this change affected the long-term eGFR slope in a retrospective cohort from the multicenter Japan Primary Aldosteronism Study. We allocated patients with primary aldosteronism to the adrenalectomy (n=202) and MR (mineralocorticoid receptor) antagonist (n=303) groups based on their treatment history and analyzed the association between the initial eGFR fall and long-term eGFR slope. The increased age, low serum potassium levels, high eGFR, and high plasma aldosterone levels were independent predictors for a large initial eGFR fall in both groups. Our analysis of tertiles based on the initial eGFR fall revealed that in the MR antagonist group, patients with a small initial eGFR fall had a significantly steeper long-term eGFR slope than those with a large initial fall (tertile 1 versus 2, P =0.025; tertile 1 versus 3, P =0.017). These associations were not identified in the adrenalectomy group. Thus, the smaller the acute fall in eGFR by initiation of MR antagonists, the greater was the rate of long-term eGFR decline. While the acute fall in eGFR induced by primary aldosteronism-specific treatment is occasionally a clinical concern, our findings highlight the favorable implications of the acute fall with respect to long-term renal outcomes.

Objectives Because of the influence on the renin-angiotensin-aldosterone system, it is recommended to avoid, if possible, the use of angiotensin-converting-enzyme inhibitors, angiotensin II type 1 receptor blockers, diuretics, β-blockers, and mineralocorticoid receptor antagonists during the diagnostic period of primary aldosteronism. A laterality index more than 4 in adrenocorticotropic hormone (ACTH)-stimulated adrenal venous sampling (ACTH-AVS) is a widely used classification of the unilateral subtype that can benefit from adrenalectomy. Here, we revealed clinical features of patients taking drugs that could affect the primary aldosteronism diagnosis (DAPD) and investigated whether the classification with laterality index more than 4 in ACTH-AVS is applicable to these patients. Patients and methods Using a large database of primary aldosteronism patients in Japan, we analyzed 2122 patients with successful ACTH-AVS. Results Patients who received any DAPD (n = 209) showed higher prevalence of comorbidity burdens and took more antihypertensive drugs compared with patients without DAPD. In patients taking DAPD, those with laterality index more than 4 had a higher prevalence of hypokalemia, a higher aldosterone-to-renin ratio and a higher prevalence of adrenal mass than those with laterality index of 4 or less. Adrenalectomy was performed in 76% patients with laterality index more than 4 and 20% with laterality index of 4 or less. Patients who underwent adrenalectomy showed biochemical cure in 89% with laterality index more than 4 and 50% with laterality index of 4 or less (P = 0.001). Multivariate regression analysis showed that laterality index more than 4 was an independent predictor of a biochemical cure. Biochemical cure rate in patients with laterality index more than 4 was consistently high, irrespective of the potential effect of individual DAPD on laterality index. Conclusion Our findings suggest that in primary aldosteronism patients to whom DAPD were administrated due to severe clinical features, laterality index more than 4 in ACTH-AVS could accurately predict a biochemical cure after adrenalectomy.

The Japan Endocrine Society (JES) has the largest ratio of female membership among societies associated with Internal Medicine in Japan; half of female members are in their 20s or 30s at present. In 2009, JES organized the "JES-We-Can" committee to promote women's career development. To evaluate the effectiveness of JES-We-Can, we investigated the gender balance of various activities at JES in fiscal 2009 and 2017. Significant gender-differences were not observed in the acquisition rate of board-certified endocrinologists (BCEs) aged

Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥65 years) and 702 younger patients (

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K + ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations

Background Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that has been investigated as a potential chemopreventive and chemotherapeutic agent. However, the antitumor efficacy and mechanisms of TGZ in pancreatic cancer have not been extensively investigated. This study was performed to investigate the in vitro and in vivo effects of TGZ against pancreatic cancer cell lines, as well as its action mechanisms in terms of PPARγ dependency and the Akt and mitogen-activated protein kinase (MAPK) pathways. We also evaluated the effects of TGZ on cell invasion and migration. Methods MIA Paca2 and PANC-1 human pancreatic cancer cell lines were used. Cell viability and caspase-3 activity were detected using fluorescent reagents, and chromatin condensation was observed after staining the cells with Hoechst 33342. Protein expression levels were detected by western blot analysis. Invasion and migration assays were performed using 24-well chambers. The in vivo antitumor effects of TGZ were investigated in nude mice inoculated with MIA Paca2 cells. Mice were orally administered TGZ (200 mg/kg) every day for 5 weeks, and tumor volumes were measured bi-dimensionally. Results TGZ showed dose-dependent cytotoxicity against both cell lines, which was not attenuated by a PPARγ inhibitor. Further, TGZ induced chromatin condensation, elevated caspase-3 activity, and increased Bax/Bcl-2 relative expression in MIA Paca2 cells. TGZ also increased phosphorylation of Akt and MAPK (ERK/p38/JNK) in both cell lines, and a JNK inhibitor significantly increased the viability of MIA Paca2 cells. TGZ moderately inhibited cell migration. Tumor growth in the MIA Paca2 xenograft model was inhibited by TGZ administration, while mouse body weights in the treated group were not different from those of the vehicle administration group. Conclusion We demonstrated for the first time the in vivo antitumor effects of TGZ in pancreatic cancer without marked adverse effects. TGZ induced mitochondria-mediated apoptosis in MIA Paca2 cells, and its cytotoxic effects were PPARγ-independent and occurred via the JNK pathway. Our results indicate that TGZ is a potential approach for the treatment of pancreatic cancer and warrants further studies regarding its detailed mechanisms and clinical efficacy.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Adrenal vein sampling (AVS) is an established method for finding patients with the unilateral subtype of PA, for which adrenalectomy is an applicable treatment. In this study, we analyzed a large database of patients with PA who underwent adrenal vein sampling, to investigate the sex differences in the impact of age at diagnosis on the subtype and cause of PA. In 2122 patients, women with the unilateral subtype were younger than men with the same subtype and women with the bilateral subtype. Younger age and older age were associated with unilateral PA in women and men, respectively. After stratification by tertiles of age, there was a trend of decreased and increased incidence of unilateral PA with aging in women and men, respectively. Male sex was a predictor of unilateral PA in middle-aged and older patients but not in younger patients. We also found that obesity, a known factor associated with idiopathic hyperaldosteronism, was positively associated with bilateral PA in younger patients but not in older patients. These findings suggest that the proportion of operable patients with unilateral PA differs depending on the combination of sex and age, and that other than obesity, the cause of PA is also associated with the bilateral subtype in older patients.

Objectives Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. Methods Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). Results At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. Conclusion Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.

Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004-2011 to 2011-2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

OBJECTIVE To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. RESEARCH DESIGN AND METHODS The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ≥6.5% [≥48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia ( RESULTS Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30–69 years. Logistic regression or χ2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

Primary aldosteronism (PA) in the elderly has increased in importance in association with population aging.To investigate the characteristics and outcomes of elderly patients with PA undergoing adrenalectomy.Using a database of patients with PA who underwent adrenal venous sampling (AVS), we compared elderly patients (≥65 years old) with nonelderly patients (65 years old) in terms of characteristics, subtype classification in ACTH-stimulated AVS, and outcomes after adrenalectomy.The elderly group had a higher prevalence of comorbidities than the nonelderly group. The proportion of the unilateral subtype [defined as a lateralization index (LI)4] was comparable between the age groups. In patients who received adrenalectomy, biochemical cure was comparable between the groups, whereas persistent hypertension was more common in the elderly group. The prevalences of hyperkalemia and renal impairment (chronic kidney disease stage 3b or higher) were higher in the elderly group. Multiple regression analysis showed that the duration of hypertension predicted persistent hypertension and hyperkalemia and that preoperative estimated glomerular filtration rate predicted renal impairment in the elderly group. LI4 in AVS was an independent predictor of biochemical cure after adrenalectomy in the elderly group but not in the nonelderly group. Age was negatively associated with biochemical cure in patients with LI ≤4.Adrenalectomy contributes to biochemical improvement in elderly patients if determined in accordance with AVS. The treatment strategy should be determined considering the high postoperative incidence of persistent hypertension and hyperkalemia in elderly patients with a long history of hypertension or renal impairment in those with reduced renal function.

Background: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT). Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m2/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m2/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated. Results: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC-857 vs. CT-857 + TT-857, P = 0.072, Fisher's exact test, P = 0.070, Log-rank test). Conclusions: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.

Epithelial sodium channels (ENaCs) play critical roles in the maintenance of fluid and electrolyte homeostasis and their genetic abnormalities cause one type of hereditary salt-sensitive hypertension, Liddle syndrome. As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal. Nedd4L/Nedd4-2 isoforms with a C2 domain are hypothesized to be related closely to ubiquitination of ENaCs. We generated Nedd4-2 C2 domain knockout mice. We demonstrate here that loss of Nedd4-2 C2 isoform causes salt-sensitive hypertension under conditions of a high dietary salt intake in vivo. The knockout mice had reduced urinary sodium excretion, osmotic pressure and increased water intake and urine volume with marked dilatation of cortical tubules while receiving a high salt diet. To the contrary, there was no difference in metabolic data between wild-type and knockout mice receiving a normal control diet. In the absence of Nedd4-2 C2 domain, a high salt intake accelerated ENaC expression. Coimmunoprecipitation studies revealed suppressed ubiquitination for ENaC with a high salt intake. Taken together, our findings demonstrate that during a high oral salt intake the Nedd4-2 C2 protein plays a pivotal role in maintaining adaptive salt handling in the kidney.

Sympathetic nerve activity is involved in the pathogenesis of salt-sensitive hypertension. The central nervous system, which regulates sympathetic nerve activity and blood pressure, plays a pivotal role. Central sympathoexcitation is deeply involved in the pathogenesis of salt-sensitive hypertension, although the precise mechanisms have not been fully elucidated because of their complexity. The role of brain oxidative stress in sympathoexcitation has been suggested in some types of hypertensive animal models. We have shown that increased brain oxidative stress may elevate arterial pressure through central sympathoexcitation in salt-sensitive hypertension. Several other factors such as mineralocorticoid receptors, aldosterone, corticosterone, epithelial sodium channels, and angiotensin II also play important roles in central sympathetic activation, some of which can be associated with brain oxidative stress. Furthermore, brain paraventricular nucleus Gαi2-protein-mediated transduction has been recently reported as a candidate for the molecular mechanism countering the development of salt-sensitive hypertension.

Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity of troglitazone (TGZ) and its mechanisms in terms of PPARγ dependency and the p38 mitogen-activated protein kinase (MAPK) pathway in three human renal cell carcinoma (RCC) cell lines, 786-O, Caki-2 and ACHN cells. TGZ induced apoptosis and exerted cytotoxicity in a PPARγ-independent manner. We demonstrated that TGZ activated the p38 MAPK pathway and was involved in the cytotoxicity of TGZ. It was also revealed that TGZ induced G(2)/M cell cycle arrest through activation of p38 MAPK.

The aim of this study was to evaluate the renal preservation effect of ubiquinol, the reduced form of coenzyme Q10 (CoQ10).Three-week-old heminephrectomized male Sprague-Dawley rats were divided into three groups (10 animals each): diet with normal (0.3%) salt, high (8%) salt, and high salt plus 600 mg/kg body weight/day of ubiquinol, for 4 weeks. Systolic blood pressure (SBP), urinary albumin (u-alb), superoxide anion generation (lucigenin chemiluminescence) and ubiquinol levels in renal tissues were examined.Salt loading increased SBP (111.0 ± 3.6 vs. 169.4 ± 14.3 mmHg, p0.01) and u-alb (43.8 ± 28.0 vs. 2528.7 ± 1379.0 µg/day, p0.02). These changes were associated with stimulation of superoxide generation in the kidney (866.3 ± 102.8 vs. 2721.4 ± 973.3 RLU/g kidney, p0.01). However, ubiquinol decreased SBP (143.9 ± 29.0 mmHg, p0.05), u-alb (256.1 ± 122.1 µg/day, p0.02), and renal superoxide production (877.8 ± 195.6 RLU/g kidney, p0.01), associated with an increase in renal ubiquinol levels.Ubiquinol, the reduced form of CoQ10, effectively ameliorates renal function, probably due to its antioxidant effect. Thus, ubiquinol may be a candidate for the treatment of patients with kidney disease.

To investigate the association between green tea consumption and the risk of endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case-control design in Japan.The cases were 152 patients with histopathologically diagnosed EEA, and the controls were 285 healthy women who were matched for age and area of residence with individual cases. The subjects completed a questionnaire regarding health-related lifestyle and reproductive history, and a food frequency questionnaire. Odds ratios (ORs) of EEA for frequency of green tea consumption were calculated by conditional logistic regression analysis.We observed a significant inverse association between green tea consumption and the risk of EEA with a dose-response relationship. The multivariate-adjusted OR of EEA was 0.77 (95% CI: 0.37-1.58) for those in the second quartile of green tea consumption (5-6 cups/week-1 cup/day), 0.61 (0.30-1.23) in the third quartile (2-3 cups/day), and 0.33 (0.15-0.75) in the highest quartile (or = 4 cups/day), as referenced with those in the lowest quartile (or = 4 cups/week; p for trend = 0.007). This inverse association was consistently observed regardless of the presence or absence of factors such as obesity and menopause.Green tea consumption may be associated with a lower risk of EEA.

The effects of a propolis extract obtained by supercritical fluid extraction on sensitivity to chemotherapeutic agents were examined in HeLa cells and resistant sublines thereof. In addition, the actions of propolis and caffeic acid phenethyl ester (CAPE), a constituent of propolis, on the multidrug efflux transporter P-glycoprotein/MDR1, were evaluated in paclitaxel-resistant HeLa/TXL cells (MDR1-overexpressing cells). In HeLa cells, the sensitivity to paclitaxel and doxorubicin, substrates of MDR1, was unchanged in the presence of propolis. In HeLa/TXL cells, propolis increased sensitivity to these MDR1 substrates. The accumulation of Rhodamine123, also a substrate for MDR1, by HeLa/TXL cells increased in the presence of 50 microg/mL, but not 10 microg/mL, of the extract. However, the growth inhibition of HeLa/TXL cells by paclitaxel was not changed by CAPE, although the accumulation of Rhodamine123 increased significantly in the presence of 100 microm, but not 1 nM or 1 microm, CAPE. Collectively, the extract was suggested to inhibit the function of MDR1 and to increase the sensitivity to MDR1 substrates in HeLa/TXL cells, effects likely to be caused by constituents other than CAPE.

We experienced two aged patients with atherosclerotic renovascular stenosis associated with hypertension and ischemic nephropathy. Both patients exhibited sudden rise in blood pressure (BP) and progressive aggravation of renal dysfunction. In these patients, the use of contrast medium to screen for renal artery stenosis (RAS) ran the risk of further deterioration of renal function. We therefore used magnetic resonance angiography (MRA), which is less conducive to renal damage, to screen for RAS. One-sided RAS was treated by percutaneous transluminal angioplasty of the renal artery (PTRA) and stenting. As a result, BP decreased in both patients. Serum creatinine (Cr) decreased slightly in one patient, whereas, in the other, serum Cr increased transiently and then decreased and stabilized to pre-treatment levels. Thus, although it is unclear whether the combination of PTRA and stenting is among the best treatments for patients with RAS and moderate-to-severe renal dysfunction, PTRA and stenting are clearly of benefit in selected patients. In addition, recent progress in characterizing the pathophysiology of ischemic nephropathy associated with renovascular hypertension has created interest in the therapeutic potential of angiotensin II receptor antagonists, sympatholytic agents, and antioxidants. Therefore, we discuss the therapeutic utility of PTRA and stenting and the above-mentioned medications in patients with RAS and renal dysfunction. (Hypertens Res 2004; 27: 985-992)

Sequence analysis of the Lutzomyia (Lu.) ayacuchensis salivary gland cDNA library identified a short peptide containing an RGD (Arg-Gly-Asp) sequence flanked by two cysteine residues in the C-terminal end as the most abundant transcript. In the present study, a recombinant protein of the RGD-containing peptide, designated ayadualin, was expressed in Escherichia colt and its activity was characterized. Ayadualin inhibited both collagen and ADP-induced platelet aggregations by interfering with the binding of integrin alpha(IIb)beta(3) to fibrinogen. The RGD sequence and cysteine residues located on both sides of the RGD sequence were essential for the inhibitory action. Moreover, ayadualin efficiently inhibited the intrinsic blood coagulation pathway irrespective of the RGD sequence. Measuring the enzymatic activity of coagulation factors using chromogenic substrates revealed that ayadualin efficiently inhibited factor XIIa (FXIIa) activity in a dose-dependent manner. In addition, pre-incubation of ayadualin with FXII inhibited FXIIa activity, while activated FXIIa was not affected by ayadualin, indicating that ayadualin inhibits the activation of FXII, but not enzymatic activity of FXIIa. These results indicated that ayadualin plays an important role in the blood feeding of Lu. ayacuchensis by inhibiting host hemostasis via dual mechanisms. (C) 2015 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Introduction: Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity and action mechanisms of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous ligands for PPARγ, in terms of PPARγ-dependency and the mitogen-activated protein kinase (MAPK) and Akt pathway in three human renal cell carcinoma (RCC)-derived cell lines. Methods: 786-O, Caki-2 and ACHN cells were used as human RCC-derived cell lines. Cell viability and caspase-3 activity was detected by fluorescent reagents, and chromatin-condensation was observed with a brightfield fluorescent microscope after staining cells with Hoechst33342. The expression levels of proteins were detected by Western blot analysis. Results: 15d-PGJ2 showed cytotoxicity in dose-dependent manner. 15d-PGJ2 induced chromatin-condensation and elevated caspase-3 activity, and the cell viability was restored by co-treatment with a pan-caspase inhibitor, Z-VAD-FMK, indicating the involvement of caspase-dependent apoptosis. The cytotoxicity was not impaired by a PPARγ inhibitor, GW9662, suggesting that 15d-PGJ2 exerted the cytotoxicity in a PPARγ-independent manner. Some antioxidants rescued cells from cell death induced by 15d-PGJ2, but some did not, suggesting that reactive oxygen species (ROS) did not contribute to the apoptosis. 15d-PGJ2 also increased the expression levels of phospho-c-Jun N terminal kinase (JNK) in Caki-2 cells, and decreased those of phospho-Akt in 786-O cells, indicating that the JNK MAPK and the Akt pathways participated in the anticancer effects of 15d-PGJ2 in some cell lines. Conclusion: 15d-PGJ2 exerted cytotoxic effects accompanying caspase-dependent apoptosis, and this effect was elicited in a PPARγ-independent manner in three cell lines. In addition, the JNK MAPK and Akt pathway was involved in the cytotoxicity of 15d-PGJ2 to some extent in some cell line. Therefore, our study showed the 15d-PGJ2 to potentially be an interesting approach for RCC treatment.

Renal cell carcinoma (RCC) has been shown to be resistant to chemotherapy and radiotherapy. In order to examine the potential of zoledronate (ZOL), a bisphosphonate, as an anticancer agent, we investigated the effects of ZOL on RCC cells and the involvement of the mevalonate pathway in antiproliferative effects, as well as the effects of ZOL administration on mice inoculated with RCC. ACHN cells were used and cell viability was measured via intra-cellular reductase activity. Chromatin condensation was detected by Hoechst 33342 staining. Proteins were detected by western blot analysis. Tumor volume was measured bidimensionally in mice inoculated with ACHN cells after vehicle or ZOL subcutaneous administration. ZOL exhibited antiproliferative effects with an IC50 value of 2.29±0.53 µM in ACHN cells and chromatin condensation was observed when treated with ZOL. Farnesol (FOH) and geranylgeraniol (GGOH), precursors of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, exhibited potency to rescue cells treated with ZOL. Additionally, Ras and RhoA proteins located in the membrane fraction decreased when treated with ZOL and recovered by FOH or GGOH treatment, suggesting that ZOL inhibited the mevalonate pathway, thereby suppressing the translocation of prenylated Ras and RhoA proteins to membrane fractions. An in vivo study showed the inhibitory potential of ZOL on tumor growth in mice without changes in body weight. Our study showed that ZOL could be useful as an anticancer agent for the treatment of RCC, and the mevalonate pathway could be an efficient target for novel therapeutic agents against RCC.

Dialysis-related amyloidosis (DRA) is one of the major complications often seen in long-term dialysis patients, and is one of the factors that decreases quality of life. β2-microglobulin (β2-m) is considered to be a major pathogenic factor in dialysis-related amyloidosis. The Lixelle adsorbent column, with various capacities, has been developed to adsorb β2-m from the circulating blood of patients with dialysis-related amyloidosis. Using a minimum type of β2-m-adsorbing column (Lixelle S-15), we evaluated its therapeutic efficacy and safety in dialysis patients. Seventeen hemodialysis patients with DRA were treated with the S-15 column for one year. Treatment was performed three times a week in this study. During the study period, pinch strength, visual analog scale for joint pain, and activities of daily living were evaluated every three months, and blood sampling was performed every six months. After one year's treatment with the S-15 column, the β2-m level decreased from 29.3±9.6mg/L to 24.7±5.1mg/L (P0.05), and the high sensitive C-reactive protein level decreased from 2996±4380ng/mL to 1292±1774ng/mL. After one year of S-15 column use, pinch strength increased from 5.9±3.0pounds to 7.2±3.2pounds (P0.05), and the visual analog scale for joint pain and activities of daily living score also improved. Long-term use of the Lixelle S-15 column is safe and effective for improvement of quality of life in chronic dialysis patients. Improvement of chronic inflammation may be one of the mechanisms through which the beneficial effects of the column is effected.

Aim Combination chemotherapy for treating cancer often is superior in clinical efficacy to monotherapy. The aim of this study was to investigate the schedule-dependent effect of 5-fluorouracil (5-FU) and platinum derivatives (cisplatin or oxaliplatin) in colorectal cancer (CRC) cell lines, and to explore factors affecting it. Methods Two human CRC-derived cell lines, DLD-1 and HCT116, were used. Three treatment schedules were tested, and growth inhibitory effects were evaluated with a WST-1 assay. Combined effects were assessed with isobolograms and a combination index. Cellular accumulation and DNA-binding of platinum were measured with inductively coupled plasma mass spectrometry. Results Exposure to 5-FU followed by cisplatin produced synergistic effects in DLD-1 cells, and the amount of platinum bound to DNA was substantially increased as compared with that for other schedules. 5-FU and oxaliplatin also tended to be synergistic when 5-FU was given first, but no significant change in the cellular kinetics of platinum was observed. On the other hand, in HCT116 cells, the combined effects of 5-FU and platinum derivatives were comparable among the three schedules. Conclusion Exposure to 5-FU followed by cisplatin had a synergistic effect in DLD-1 cells, suggesting that the amount of platinum bound to DNA contributes to this result. Also, the effect was dependent on the type of platinum derivative and cell.

1. There are multiple and complex mechanisms of salt-induced hypertension; however, central sympathoexcitation plays an important role. In addition, the production of reactive oxygen species (ROS) is increased in salt-sensitive hypertensive humans and animals. Thus, we hypothesized that brain ROS overproduction may increase blood pressure (BP) by central sympathostimulation. 2. Recently, we demonstrated that ROS levels were elevated in the hypothalamus of salt-sensitive hypertensive animals. Moreover, intracerebroventricular anti-oxidants suppressed BP and renal sympathetic nerve activity more in salt-sensitive than non-salt-sensitive hypertensive rats. Thus, brain ROS overproduction increased BP through central sympathoexcitation in salt-sensitive hypertension. 3. Salt sensitivity of BP is enhanced in obesity and metabolic syndrome. Interestingly, it is also suggested that, in obesity-induced hypertension models, increases in BP are caused by brain ROS-induced central sympathoexcitation. 4. Recent studies suggest that increased ROS production in the brain and central sympathoexcitation may share a common pathway that increases BP in both salt- and obesity-induced hypertension.

Background Currently definitive 5-fluorouracil (5-FU)/cisplatin (CDDP) -based chemotherapy is recognized as one of the most promising treatments for esophageal cancer. A series of studies performed found genetic polymorphisms and the plasma concentration of 5-FU to be predictive of acute severe toxicities and clinical response. Genetic polymorphisms of tumor necrosis factor (TNF) -α and its surface receptors, TNFRSF1A and TNFRSF1B have been examined in terms of susceptibility to various cancers. In this study, genetic polymorphisms of TNFRSF1B gene were evaluated Japanese esophageal squamous cell carcinoma (ESCC) patients treated with the definitive 5-FU/CDDP-based chemoradiotherapy and their predictive values of prognosis or severe acute toxicities were assessed. Methods Forty-six patients with ESCC were treated with the definitive 5-FU/CDDP-based chemoradiotherapy, one course of which consisted of the continuous infusion of 5-FU for days 1-5 and 8-12, the infusion of CDDP on days 1 and 8, and the radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course repeated after 2-week interval. Genetic polymorphisms of a TNF-α receptor TNFRSF1B gene were determined by a TaqMan® MGB probe-based polymerase chain reaction. Results The genotype of TNFSR1B A1466G, but not M196R/T587G or C1493T, was found to be predictive of clinical response, i.e., a complete response or not (p = 0.040). Clinical response was predicted by tumor size (p = 0,002), lymph node metastasis (p = 0.007), distant metastasis (p = 0.001) and disease stage (p < 0.001), but TNFRSF1B A1466G genotype was independent of these factors. Conclusions Genetic polymorphism of TNFRSF1B A1466G was found to be predictive response in Japanese ESCC patients with a definitive 5-FU/CDDP-based chemoradiotherapy. Further clinical investigation with a large number of patients or experiments in vitro should be performed to assess the predictive value of TNFRSF1B A1466G genotype after chemoradiotherapy.

During recent decades, the incidence of gynecologic cancers, i.e., cancers of the cervix, endometrium and ovary, has increased in Japan. However, risk factors of gynecologic cancers have not been fully clarified in Japan. To investigate common and site-specific risk factors among gynecologic cancers, we conducted a hospital-based case-control study. The cases, i.e., 151 cervical, 103 endometrial and 141 ovarian cancer cases and the controls (n = 2016) were selected from female patients aged 30 and over, who were admitted to a single hospital in Miyagi Prefecture from 1997 to 2003. Information on reproductive factors, exogenous hormone use, and lifestyles including smoking was collected using a self-administered questionnaire. Smoking was significantly associated with an increased risk of cervical cancer. A dose-response relationship with the number of cigarettes per day was also observed (p for trend = 0.004). Older age at menarche was associated with a decreased risk of endometrial and ovarian cancers. For these cancers, the decreased risk was detected with increasing parity number (endometrium, p for trend = 0.0001; ovary, p = 0.0002). There was no significant association between exogenous hormone use and gynecologic cancer risk. The results indicate that smoking is a major risk factor of cervical cancer. In addition, hormonal factors, which are related to early onset of menarche and low parity, are common risk factors for endometrial and ovarian cancers. The increase in female smokers and the decrease in fertility rate may contribute to the increase in gynecologic cancer incidence in Japan.

It is well known that high salt intake induces hypertension and cardiovascular damage, while dietary potassium supplementation counteracts these harmful effects. Actually, the protective effect of potassium is strengthened with excess salt as compared with salt depletion. Although the precise mechanisms have not been fully elucidated, in our previous reports, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in salt-sensitive hypertension. Also, potassium supplement suppressed salt-induced insulin resistance. These effects of dietary potassium can explain its cardio- and vasculo-protective action in addition to the potassium supplementation induced decreased salt-induced rise in blood pressure. On the other hand, salt-sensitive hypertension is associated with reactive oxygen species (ROS) overproduction. Moreover, sympathoexcitation can be induced by central ROS upregulation and insulin resistance can be caused by ROS excess in the target organs of insulin, such as skeletal muscle. Conversely, the seemingly different actions of potassium can be explained by the antioxidant effect of dietary potassium; in our recent studies, potassium supplementation inhibits salt-induced progress of cardiac diastolic dysfunction and vascular neointima formation by cuff placement around arteries, associated with the inhibition of regional ROS overproduction, in salt-sensitive hypertension. Thus, it is possible that dietary potassium protects against salt-induced cardiovascular damage by the reduction of ROS generation and by central sympatholytic action and amelioration of insulin resistance induced through its antioxidant effect.

The purpose of this study was to examine the effect of a new thermal cycling method using PCR thermal cycler on the durability of two-step self-etching adhesive systems. Beam specimens for microtensile bond strength test were inserted into PCR tubes with distilled water. Thermal cycling (0, 1000, 2000, and 3000 cycles) was done with the PCR program at two different temperatures of 5 and 55 degrees C for 30 seconds each using a PCR thermal cycler. After thermal cycling, specimens were subjected to microtensile bond strength test and fractured surfaces were observed by SEM. The bond strength of Imperva Fluoro Bond after 3000 times of thermal cycling was significantly decreased compared to those of less than 2000 cycles (p0.05), whereas SI-R20401 showed no significant differences even after 3000 cycles (p0.05). Results of this study revealed that bond strength was affected by the thermal stress introduced in this experimental model. Therefore, this new thermal cycling method is a potentially useful and accessible means to evaluate the durability of dentin adhesive systems.

This study evaluated color and translucency changes caused by light curing resin composite materials.The CIELAB parameters (L*, a* and b*) of disks of A2 and opaque A2 shades of Charisma (Heraeus-Kulzer), Solare (GC) and Filtek Supreme (3M) were evaluated on the backings of black, white and the material itself both before and after light curing to evaluate color and translucency changes (by means of calculating deltaE* and the translucency parameter, respectively).Solare and Filtek Supreme showed significantly smaller color changes during light curing than Charisma; however, the value of deltaE* of all the products/shades was still in the clinically unacceptable range. Regarding translucency changes during light curing, the A2 and opaque A2 shades of Charisma showed a statistically significant increase, although no difference was observed in the other products.Solare and Filtek Supreme tended to show less changes in translucency and color during light curing compared to Charisma. Nevertheless, the changes in color during light curing were still in the range of unacceptable color change. Therefore, direct shade matching of these materials for a precise shade match should be performed by using the cured material.

The purpose of this pilot study was to evaluate the effects of baby massage for 3 months after delivery on mothers' mood status and salivary cortisol level. Study participants were a convenient sample of mothers who delivered their babies at a hospital in Japan, and were recruited at the time of the routine 5-6 weeks postnatal visit to the pediatric office. Thirty-nine mothers were randomly assigned to experimental and control groups. Nineteen mothers in the experimental group were examined before the first day of the baby massage, and 3 months after delivery. The psychological measurements used were profile of mood states (POMS). In the physiological measurements, the salivary cortisol level was analyzed. The result revealed that significant differences in the POMS score were seen in depression and vigor between the two groups at 3 months. There were no significant differences in the salivary cortisol levels. Baby massage was found to positively affect the mood status of the mothers. We propose that midwives and other health-care professionals should recommend mothers to do baby massage to improve their own mood status.

The purpose of this study was to evaluate the optical properties--not only the translucency but also the colours--of opaque-shade resin composites. The CIELAB parameters (L*, a* and b*) of disks of A2 and opaque A2 (OA2) shades of Charisma (Heraeus-Kulzer), Solare (GC) and Filtek Supreme (3M) were evaluated on backings of black, white and the material itself to calculate the translucency parameter (TP) and the colour differences (delta E*) between A2 and OA2. A two-way analysis of variance (anova) for the TP indicated a less statistically significant TP value in the OA2 shade than the A2 shade for all products. As for the products, Charisma showed a statistically greater TP value than the other two products. Regarding the delta E* between A2 and OA2, all the products revealed clinically perceptible colour differences (delta E* > 3.3). Hence, we must take the colour differences of opaque-shade resin composites into consideration, as well as the translucency of the materials, for a clinically acceptable colour match of the restoration.

15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) is one of factors contributed to the neurotoxicity of amyloid β (Aβ), a causative protein of Alzheimer's disease. Type 2 receptor for prostaglandin D(2) (DP2) and peroxysome-proliferator activated receptorγ (PPARγ) are identified as the membrane receptor and the nuclear receptor for 15d-PGJ(2), respectively. Previously, we reported that the cytotoxicity of 15d-PGJ(2) was independent of DP2 and PPARγ, and suggested that 15d-PGJ(2) induced apoptosis through the novel specific binding sites of 15d-PGJ(2) different from DP2 and PPARγ. To relate the cytotoxicity of 15d-PGJ(2) to amyloidoses, we performed binding assay [(3)H]15d-PGJ(2) and specified targets for 15d-PGJ(2) associated with cytotoxicity. In the various cell lines, there was a close correlation between the susceptibilities to 15d-PGJ(2) and fibrillar Aβ. Specific binding sites of [(3)H]15d-PGJ(2) were detected in rat cortical neurons and human bronchial smooth muscle cells. When the binding assay was performed in subcellular fractions of neurons, the specific binding sites of [(3)H]15d-PGJ(2) were detected in plasma membrane, nuclear and cytosol, but not in microsome. A proteomic approach was used to identify protein targets for 15d-PGJ(2) in the plasma membrane. By using biotinylated 15d-PGJ(2), eleven proteins were identified as biotin-positive spots and classified into three different functional proteins: glycolytic enzymes (Enolase2, pyruvate kinase M1 (PKM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)), molecular chaperones (heat shock protein 8 and T-complex protein 1 subunit α), cytoskeletal proteins (Actin β, F-actin-capping protein, Tubulin β and Internexin α). GAPDH, PKM1 and Tubulin β are Aβ-interacting proteins. Thus, the present study suggested that 15d-PGJ(2) plays an important role in amyloidoses not only in the central nervous system but also in the peripheral tissues.

Background Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults. Methods Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2–3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4–0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6–1.0 mg/kg/day) alone. Results The length of hospital stay was the shortest in Group 1 (P

Background Tolvaptan, a vasopressin V2 receptor blocker, has a diuretic effect for patients with heart failure. However, there were a few data concerning the effects of tolvaptan in patients with chronic kidney disease (CKD). Methods We retrospectively analyzed 21 patients with chronic heart failure and CKD. Tolvaptan was co-administered with other diuretics in-use, every day. We compared clinical parameters before and after the treatments with tolvaptan. Furthermore, we examined the correlations between baseline data and the change of body weight. Results Tolvaptan decreased the body weight and increased the urine volume (p = 0.001). The urine osmolality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Serum creatinine increased slightly after 1 week of treatment (p = 0.012). The alteration of body weight within the study period correlated negatively with the baseline urine osmolality (r = −0.479, p = 0.038), the baseline urine volume (r = −0.48, p = 0.028), and the baseline inferior vena cava diameter (IVCD) (r = −0.622, p = 0.017). Hyponatremia was improved to the normal value, and the augmentations of the sodium concentration were negatively associated with the basal sodium levels (p = 0.01, r = −0.546). Conclusions Tolvaptan is effective in increasing diuresis and improved hyponatremia, even in patients with CKD. The baseline urine osmolality, urine volume, and IVCD may be useful predictors for diuretic effects of tolvaptan.