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Protective effects of tolvaptan against worsening renal function in acute heart failure have been shown. However, long-term effects of its agent on renal function remain to be elucidated. The present study investigated retrospectively whether long-term treatment with tolvaptan exerts renoprotective effects in patients with chronic heart failure, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after tolvaptan administration. From 63 outpatients with chronic heart failure taking diuretics including tolvaptan, 34 patients whose eGFR levels were continuously measured for more than 6 months both before and after administration of tolvaptan (average dose, 7.8 mg/day at the end of the follow-up period) were selected as eligible for the present analyses. All eGFR values were separately plotted before and after the initiation of treatment with tolvaptan (except hospitalization periods) along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. The mean follow-up periods before and after tolvaptan administration were 1197 and 784 days (3.3 and 2.1 years), respectively. Changing rates of eGFR per year were significantly ameliorated after treatment with tolvaptan (mean ± SD, − 8.02 ± 9.35 to − 1.62 ± 5.09 mL/min/1.73m2 /year, P = 0.001). In echocardiographic parameters, inferior vena cava (IVC) diameter significantly decreased after tolvaptan administration, and the decrease in IVC diameter was correlated with the improvement of eGFR decline slope after administration of tolvaptan (P = 0.0075). This longitudinal observational study indicated that long-term treatment with tolvaptan ameliorated annual decline in eGFR in outpatients with chronic heart failure. Our findings suggest that tolvaptan has a protective effect against chronically worsening renal function in heart failure patients.

We have identified the cyclin domain-containing proteins encoded by the genomes of 17 species ofAspergillusas well as 15 members of other genera of filamentous ascomycetes. Phylogenetic analyses reveal that the cyclins fall into three groups, as in other eukaryotic phyla, and, more significantly, that they are remarkably conserved in these fungi. All 32 species examined, for example, have three group I cyclins, cyclins that are particularly important because they regulate the cell cycle, and these are highly conserved. Within the group I cyclins there are three distinct clades, and each fungus has a single member of each clade. These findings are in marked contrast to the yeastsSaccharomyces cerevisiae, Schizosaccharomyces pombe, andCandida albicans, which have more numerous group I cyclins. These results indicate that findings on cyclin function made with a modelAspergillusspecies, such asA. nidulans, are likely to apply to other Aspergilli and be informative for a broad range of filamentous ascomycetes. In this regard, we note that the functions of only oneAspergillusgroup I cyclin have been analysed (NimECyclin BofA. nidulans). We have consequently carried out an analysis of the members of the other two clades usingA. nidulansas our model. We have found that one of these cyclins, PucA, is essential, but deletion of PucA in a strain carrying a deletion of CdhA, an activator of the anaphase promoting complex/cyclosome (APC/C), is not lethal. These data, coupled with data from heterokaryon rescue experiments, indicate that PucA is an essential G1/S cyclin that is required for the inactivation of the APC/C-CdhA, which, in turn, allows the initiation of the S phase of the cell cycle. Our data also reveal that PucA has additional, non-essential, roles in the cell cycle in interphase. TheA. nidulansmember of the third clade (AN2137) has not previously been named or analyzed. We designate this geneclbA. ClbA localizes to kinetochores from mid G2 until just prior to chromosomal condensation. Deletion ofclbAdoes not affect viability. However, by using a regulatable promoter system new toAspergillus, we have found that expression of a version of ClbA in which the destruction box sequences have been removed is lethal and causes a mitotic arrest and a high frequency of non-disjunction. Thus, although ClbA is not essential, its timely destruction is essential for viability, chromosomal disjunction, and successful completion of mitosis.

Attenuated plaque on intravascular ultrasound (IVUS) and low attenuation plaque on computed tomography angiography (CTA) are associated with no-reflow phenomenon during percutaneous coronary intervention (PCI). However, evaluation by a single modality has been unable to satisfactorily predict this phenomenon. We investigated whether the combination of IVUS and CTA findings can ameliorate the predictive potential for no-reflow phenomenon after stent implantation during PCI in stable coronary artery disease (CAD). A total of 988 lesions of 707 stable CAD patients who underwent coronary CTA before PCI were enrolled. PCI was performed with preprocedural IVUS and stent implantation. As for plaque characters, very low attenuation plaque (CTA v-LAP) whose minimum density was

It is still controversial whether treatment with renin-angiotensin system (RAS) inhibitors reduces the risk of incident atrial fibrillation (AF). This longitudinal observational study was performed to investigate the confounder-independent effects of RAS inhibitors on new-onset AF in hypertensive patients. Among 1263 consecutive hypertensive patients who underwent echocardiography, 964 eligible patients (mean age, 63 years) were enrolled as the study population. Forty-nine patients developed new-onset AF during the follow-up period (mean: 4.6 years). Kaplan-Meier analysis showed that the cumulative AF event rate was lower in patients receiving RAS inhibitors than in patients without these drugs, but the difference between these two groups was not significant (P=0.057). Since the use of RAS inhibitors was influenced by concomitant diabetes, chronic kidney disease and left ventricular hypertrophy, propensity score matching (1:1) was employed to minimize the influence of selection bias for RAS inhibitors. Clinical and echocardiographic parameters showed no significant differences between the propensity score-matched groups with and without RAS inhibitor therapy (both n=326), but the cumulative AF event rate was significantly lower in the group receiving RAS inhibitors (P=0.013). Univariate and multivariate Cox regression analyses also revealed that RAS inhibitor therapy was associated with a significantly lower risk of new-onset AF during the follow-up period. In conclusion, this propensity score matching study demonstrated that the incidence of new-onset AF was lower in hypertensive patients receiving RAS inhibitor therapy.

Purpose Based on heating tests and load-bearing fire tests, this paper aims to discuss the charring rate, the temperature distribution in the section and the load-bearing capacity of structural glued laminated timber beams not only during the heating phase during a 1-h standard fire in accordance with ISO 834-1 but also during the cooling phase. Design/methodology/approach Heating tests were carried out to confirm the charring rate and the temperature distribution in the cross-section of the beams. Loading tests under fire conditions were carried out to obtain the load-deformation behavior (i.e. the stiffness, maximum load and ductility) of the beam. Findings The temperature at the centroid reached approximately 30°C after 1 h and then increased gradually until reaching 110-200°C after 4 h, during the cooling phase. The maximum load of the specimen exposed to a 1-h standard fire was reduced to approximately 30 per cent of that of the specimen at ambient temperature. The maximum load of the specimen exposed to a 1-h standard fire and 3 h of natural cooling in the furnace was reduced to approximately 14 per cent. In case of taking into consideration of the strength reduction at elevated temperature, the reduction ratio of the calculated bending resistance agreed with that of the test results during not only heating phase but also cooling phase. Originality/value The results of this study state that it is possible to study on strength reduction in cooling phase for end of heating, timber structural which has not been clarified. It is believed that it is possible to appropriately evaluate the fire performance, including the cooling phase of the timber structural.

OBJECTIVE The present study aimed to compare circadian hemodynamic characteristics in hypertensive patients with and without primary aldosteronism. METHODS Circadian hemodynamics, including 24-h brachial and central blood pressure (BP), SBP variability indices, central pulse wave velocity (PWV), augmentation index (AIx@75), cardiac index, and total vascular resistance (TVR), were evaluated using an oscillometric device, Mobil-O-Graph, in 60 patients with primary aldosteronism (63.4±13.3 years, 47% women) and 120 age-matched and sex-matched patients with essential hypertension. RESULTS Office SBP, PWV, AIx@75, and BP variability indices were similar between groups; however, 24-h brachial (124 ± 14 vs 130 ± 11 mmHg) as well as central (112 ± 12 vs 120 ± 10 mmHg) SBP was higher (both P

Background. The results of recent trials have brought some confusion to the treatment strategy for renal artery stenosis (RAS). To evaluate the applicability of percutaneous transluminal renal angioplasty (PTRA) for RAS, we extracted the factors that may affect the effectiveness of PTRA from cases experienced at a hypertension center. Methods and Results. We retrospectively assessed the blood pressure (BP) lowering effects and renoprotective effects in 50 consecutive patients that had hemodynamically significant RAS and had undergone PTRA and stenting during 2001–2005. Subjects were diagnosed with atherosclerotic RAS (42), fibromuscular dysplasia (6), or Takayasu disease (2). After PTRA, BP significantly lowered from 152.3/80.3 mmHg to 132.6/73.2 mmHg (p<0.05), but the estimated glomerular filtration rate (eGFR) did not change significantly. There were no factors associated with the BP lowering effects of PTRA. The baseline resistive index (RI) was negatively correlated with the change in eGFR (p<0.05). After correction for age, sex, BMI, and the dose of contrast medium, the association of RI with change in eGFR remained significant. Conclusion. In cases with hemodynamically significant RAS, PTRA lowered BP but was not effective in improving renal function. Higher baseline RI may be a factor for predicting poor clinical course of renal function after PTRA.

We investigated the impact of renal function on outcomes after percutaneous transluminal angioplasty.A total of 139 hypertensive patients with atherosclerotic renal artery stenosis (mean age, 70 years, 80.6% men) who underwent renal percutaneous transluminal angioplasty were included. Renal function was evaluated on the basis of estimated glomerular filtration rate (eGFR) and albuminuria/proteinuria, and classified into three categories according to eGFR (≥45, 30-44, and30 ml/min/1.73 m) and albuminuria/proteinuria [normal-to-mild: albumin/creatinine ratio (ACR) less than 3.0, protein/creatinine ratio (PCR) less than 15; moderate: ACR 3.0-30.0, PCR 15-50; severe: ACR 30.0, PCR 50 mg/mmol].During a median follow-up of 5.4 years, 36.0% of patients developed the primary composite end point, including cardiovascular and renal outcomes. In multivariate Cox regression analysis, eGFR less than 30 (hazard ratio 3.47, P 0.01) as well as severe albuminuria/proteinuria (hazard ratio 2.63, P 0.05) was an independent predictor of worse outcome. In the subgroup without events within 1 year after angioplasty (n = 117), the outcome differed among the three renal functional categories at 1 year based on eGFR (log-rank χ = 16.28, P 0.001) as well as on albuminuria/proteinuria (log-rank χ = 8.30, P 0.05). At 1 year, 24 patients (20.1%) showed at least 20% decrease in eGFR, and their outcome was worse than that in those with at least 20% increase (n = 23) (hazard ratio 3.50, P 0.05). Multiple logistic regression analysis indicated that pretreatment moderate-to-severe albuminuria/proteinuria was an independent predictor of at least 20% eGFR decrease (odds ratio 2.82, P 0.05).Impaired renal function, and in particular, a poor response of eGFR to angioplasty, is associated with worse outcome. Therapeutic effectiveness of renal angioplasty seems to be limited in patients with albuminuria/proteinuria.

This study included 126 hypertensive patients with renal artery stenosis (mean age, 63 years; 22.2% fibromuscular dysplasia [FMD]) and investigated the effects of percutaneous transluminal renal angioplasty on office and home blood pressure (BP), and BP variability estimates derived from home BP, both at baseline and up to 12 months after angioplasty. Home BP was measured for 7 consecutive days, and the threshold defining uncontrolled home BP was ≥135/85 mm Hg. In both the FMD and atherosclerotic stenosis (ARAS) groups, office and home BP decreased significantly after angioplasty (all P P P =0.11) systolic BP at 12 months was significantly greater in FMD. In both groups, all morning BP variability indices except the coefficient of variation in ARAS decreased significantly after revascularization (all P P P =0.11). The prevalence of uncontrolled home BP was 77.0% at baseline and 38.9% after revascularization. Duration of hypertension (odds ratio, 1.48), ARAS (odds ratio, 3.18), and the presence of proteinuria (odds ratio, 2.10) were independent predictors of uncontrolled home BP after revascularization (all P

Stimulation of insulin-like growth factor (IGF)-1 receptor by IGF-1 and insulin strongly induces cardiomyocyte hypertrophy. In this study, we assessed the hypothesis that genetic variations of the IGF-1 receptor may be linked to the diversity of left ventricular (LV) structure in hypertensive patients. Genotypes in 12 single nucleotide polymorphisms (SNPs) of the IGF-1 receptor gene identified by direct sequencing were determined in 795 Japanese patients with essential hypertension. In echocardiographic examinations, LV mass index (LVMI) and relative wall thickness (RWT) were measured. Among 12 SNPs, promoter −328C>T and intron-13 275124A>C polymorphisms were significantly associated with LV hypertrophy (LVMI⩾125 g m–2) and concentric change (RWT⩾0.44), respectively. In allele frequencies, the C allele of −328C>T was related to LV hypertrophy, and the A allele of 275124A>C was related to LV concentric change. In fact, LVMI and prevalence of LV hypertrophy increased in CC genotype of –328C>T. RWT and prevalence of LV concentric change increased in AA genotype of 275124A>C. A multiple logistic regression analysis revealed that the presence of CC genotype of –328C>T or AA genotype of 275124A>C was an independent determinant for LV hypertrophy or concentric change, respectively. Furthermore, the combination of CC of −328C>T and AA of 275124A>C genotypes was significantly associated with abnormal LV geometry, especially concentric hypertrophy. Our findings show that two SNPs of the IGF-1 receptor gene are related to LV hypertrophy in patients with essential hypertension, suggesting that the genetic variation of the IGF-1 receptor may be involved in the diversity of LV structure in hypertensives.

Recent studies have shown that the converse phenomenon of white-coat hypertension called 'reverse white-coat hypertension' or 'masked hypertension' is associated with poor cardiovascular prognosis. We assessed the hypothesis that this phenomenon may specifically influence left ventricular (LV) structure in treated hypertensive patients. A total of 272 outpatients (mean age, 65 years) with chronically treated essential hypertension and without remarkable white-coat effect were enrolled. Patients were classified into two groups according to office and daytime ambulatory systolic blood pressure (SBP); that is subjects without (Group 1: office SBPor =daytime SBP, n=149) and with reverse white-coat effect (Group 2: office SBPdaytime SBP, n=123). LV mass index and relative wall thickness were echocardiographically determined. In all subjects, LV mass index and relative wall thickness were positively correlated with daytime and 24-h SBP, but not with office SBP. In addition, these two indices were inversely correlated with office--daytime SBP difference. LV mass index (136+/-31 and 115+/-28 g/m(2), mean+/-s.d.) and relative wall thickness (0.49+/-0.09 and 0.46+/-0.07) were significantly greater in Group 2 than in Group 1. As for LV geometric patterns, Group 2 had a significantly higher rate of concentric hypertrophy compared with Group 1 (48 and 28%). Multivariate analyses revealed that the presence of reverse white-coat effect was a predictor for LV concentric hypertrophy, independent of age, sex, hypertension duration, antihypertensive treatment and ambulatory blood pressure levels. Our findings demonstrate that reverse white-coat effect is an independent risk factor for LV hypertrophy, especially concentric hypertrophy, in treated hypertensive patients.

Aims: It has been shown that both angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB) have renoprotective effects via mechanisms that are independent of blood pressure reduction. The aim of this study was to evaluate the intrarenal hemodynamic change with ARB by renal Doppler ultrasonography (RDU) and to assess the mechanism of ARB in patients with hypertension. Methods: Thirty hypertensive patients with renal insufficiency caused by glomerular diseases, diabetes and hypertensive nephrosclerosis were included in this study. RDU was performed before and one week after taking ARB. Resistance index (RI) (peak systolic velocity - end diastolic velocity/peak systolic velocity) in the intrarenal segmental artery were calculated, and the amounts of urinary protein or albumin were determined. Results: We defined patients whose microalbuminuria or proteinuria was reduced by greater than 30% by ARB as responders (n = 22) and defined other patients as non-responders (n = 8). There were no significant differences between the responder and non-responder groups in baseline characteristics. RI was significantly improved by ARB in the responder group, but not in the non-responder group. The reduction of RI after ARB treatment was most prominent in patients with hypertensive nephrosclerosis. Conclusions: Improvement in intrarenal hemodynamics might play an important role in the mechanisms of the renoprotective effect of ARB in patients with hypertension.

Aims Left ventricular (LV) hypertrophy and LV diastolic dysfunction are cardiac changes commonly observed in patients with chronic renal failure (CRF) as well as hypertension. Although the impairment of LV diastolic function in patients with diabetes mellitus has been shown, little is known about the specific effect of diabetes on LV diastolic function in patients with CRF. The present study was designed to investigate the impact of diabetic nephropathy on LV diastolic dysfunction, independent of LV hypertrophy, in CRF patients. Methods In 67 patients with non-dialysis CRF as a result of chronic glomerulonephritis (n = 33) or diabetic nephropathy (n = 34), and 134 hypertensive patients with normal renal function, two-dimensional and Doppler echocardiographic examinations were performed, and LV dimension, mass, systolic function, and diastolic function were evaluated. Results LV mass was increased and LV diastolic dysfunction was advanced in subjects with CRF compared with hypertensive controls. In the comparison of echocardiographic parameters between the two groups of CRF patients, i.e. chronic glomerulonephritis and diabetic nephropathy groups, all indices of LV diastolic function were more deteriorated in the diabetic nephropathy group than in the chronic glomerulonephritis group, although LV structure including hypertrophy and systolic function did not differ between the groups. In a multiple regression analysis, the presence of diabetes (i.e. diabetic nephropathy group) was a significant predictor of LV diastolic dysfunction in CRF subjects, independent of other influencing factors such as age, blood pressure, renal function, anaemia and LV hypertrophy. Conclusion The present findings suggest that LV diastolic dysfunction, independent of LV hypertrophy, is specifically and markedly progressed in patients with CRF as a result of diabetic nephropathy.

Carotid intima-media thickness (IMT) assessed by ultrasonography is regarded as an early predictor of general arteriosclerosis in patients with essential hypertension. However, the methods of measuring IMT have not been globally standardized, and it remains unclear whether conventional measurement of IMT represents the prevalence of hypertensive target organ damage. In this study, we verified the association between several commonly used carotid ultrasonographical parameters and the severity of hypertensive target organ damage (retinal arteriosclerosis, microalbuminuria, left ventricular hypertrophy (LVH)). Carotid ultrasonography, echocardiography, urinalysis, and funduscopy were performed in 184 patients (64 +/- 12 years, 96 males and 88 females) with various stages of essential hypertension. Carotid arteriosclerosis was assessed using four methodologically different methods: conventional-IMT, maximum-IMT (Max-IMT), Mean-IMT, and Plaque Score (the sum of all plaque thicknesses). Age and all carotid ultrasonographical parameters were significantly associated with albuminuria, retinal arteriosclerosis, and left ventricular mass index. High-sensitivity CRP was significantly correlated with retinopathy and LVH. Carotid parameters in patients with histories of cardiovascular events were significantly greater in those without events. Among all carotid parameters, Max-IMT showed the highest correlation coefficient of the severity of target organ damage, and showed significant association with CRP. Stepwise regression analysis revealed that Max-IMT was the independent factor for predicting target organ damage. Max-IMT is suggested to be the most reliable and simplest parameter for predicting hypertensive target organ damage including microangiopathy in patients with essential hypertension.

Blood pressure (BP) control in hypertensives has improved in recent years; however, it remains insufficient. We investigated the trend of BP control status in hypertensive patients with antihypertensive medication and salt intake. Two hundred and eight treated hypertensive patients were prospectively followed between 2007 and 2012. During this period, average clinic BP significantly decreased from 137±12/80±9 to 133±11/76±8 mmHg, and the achievement rate of BP control defined as140/90 mmHg increased from 58% to 71% (p0.01). Morning home BP also significantly decreased from 132±8/80±8 to 130±8/76±7 mmHg, and the percentage of patients with sustained hypertension (CBP≥140/90 mmHg and HBP≥135/85 mmHg) decreased from 27% to 16% (p0.05). The number of antihypertensive drugs increased significantly from 2.1±1.2 to 2.3±1.1 (p0.01), while no differences were observed in urinary salt excretion (9.0±2.4 g/day in 2007, 9.0±2.6 g/day in 2012). Office and home BP decreased and the rate of BP control increased in treated hypertensive patients in the past 5 years. Intensive pharmacological therapy, but not a reduction in salt intake appears to have contributed to improved BP control.

Sodium–copper chlorophyllin (CHL) inhibits the formation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypt foci (ACF) and tumours in the F344 rat when it is given simultaneously with either carcinogen. However

Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) glycogen synthase kinase-3β (GSK-3β), negatively regulate and 1,2-dimethylhydrazine (DMH) induce colon tumors in β-catenin (9,10). In the absence of Wnt signal, GSK-3β the rat that contain mutations in β-catenin, but the pattern phosphorylates β-catenin at critical Ser/Thr residues, targeting of mutation differs from that found in human colon cancers. it for ubiquitination by β-TrCP and proteosomal degradation In both species, mutations affect the glycogen synthase (11,12). In primary human colon tumors and colorectal cell kinase-3β consensus region of β-catenin, but whereas they lines, mutations in CTNNB1 substitute the critical Ser/Thr directly substitute critical Ser/Thr phosphorylation sites in residues in the GSK-3β region and stabilize β-catenin, leading human colon cancers, the majority of mutations cluster to the accumulation of β-catenin–TCF–LEF complexes in the around Ser33 in the rat tumors. Two dietary phytochem- nucleus (3–5). This complex is able to activate various target icals, chlorophyllin and indole-3-carbinol, given post-initi- genes, including c-MYC, c-JUN and cyclin D1 (13–15). ation, shifted the pattern of β-catenin mutations in rat In addition to genetic factors, a major risk factor for colon tumors induced by IQ and DMH. Specifically, 17/39 colorectal cancer is diet, and approximately one third of human (44%) of the β-catenin mutations in groups given carcino- colorectal cancers might be prevented through appropriate gen plus modulator were in codons 37, 41 and 45, and dietary modification (16). The human diet contains mutagens substituted critical Ser/Thr residues directly, as seen in and carcinogens, as well as cancer chemopreventive comhuman colon cancers. None of the tumors from groups pounds (17–20). Two such compounds that have been of given carcinogen alone had mutations in these codons. interest in this laboratory are indole-3-carbinol (I3C), a Interestingly, many of the mutations that substituted critical constituent of brassica vegetables, and chlorophyllin (CHL), Ser/Thr residues in β-catenin were from a single group a water-soluble salt of chlorophyll. Previous studies have given DMH and 0.001% chlorophyllin, in which a statistic- determined that during the initiation phase, I3C and CHL ally significant increase in colon tumor multiplicity was exhibit anti-carcinogenic properties by altering carcinogen observed compared with the group given DMH only. These metabolizing enzymes or via molecular complex formation, tumors had marked over-expression of cyclin D1 ,c -myc respectively (21,22). However, the post-initiation effects of and c-jun mRNA and c-Myc and c-Jun proteins were these compounds are generally less well characterized, and a strongly elevated compared with tumors containing wild- few studies have provided evidence for tumor promotion or type β-catenin. The results indicate that the pattern of β- enhancement depending upon the initiator, exposure protocol catenin mutations in rat colon tumors can be influenced and species (see refs 21 and 22 for mini-reviews). by exposure to dietary phytochemicals administered post- In this report, we examined the pattern of β-catenin mutainitiation, and that the mechanism might involve the altered tions in colon tumors from rats induced with 2-amino-3expression of β-catenin/Tcf/Lef target genes. methylimidazo[4,5-f]quinoline (IQ) or 1,2-dimethylhydrazine (DMH) and post-treated with CHL or I3C. The carcinogen DMH is a synthetic compound that induces tumors of the

Chlorophyllin (CHL) is a water-soluble derivative of chlorophyll, the ubiquitous pigment in green and leafy vegetables, whereas indole-3-carbinol (I3C) is present in cruciferous vegetables such as cabbage, broccoli and cauliflower. In rats initiated with 1,2-dimethylhydrazine (DMH), CHL and I3C reportedly promoted or enhanced the incidence of colon tumors when they were administered after, or during and after the carcinogen exposure, respectively. The same compounds given post-initiation inhibited the formation of colonic aberrant crypts induced by heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), but tumor suppression was not examined in the latter studies. In the present investigation, male F344 rats were treated with IQ or DMH during the first 5 weeks of a 1 year study; IQ was given in the diet (0.03%), whereas DMH was administered once a week by s.c. injection (20 mg/kg body wt). Beginning 1 week after the last dose of IQ or DMH until sacrifice, rats received 0.001, 0.01 or 0.1% (w/v) CHL in the drinking water or 0.001, 0.01 or 0.1% I3C in the diet. Compared with controls given carcinogen alone, 0.1% I3C treatment suppressed the multiplicity of IQ-induced colon tumors, and CHL inhibited in a dose-related manner the incidence of IQ-induced liver tumors. However, 0.001% CHL increased significantly the multiplicity of DMH-induced colon tumors while having no effect on the colon tumors induced by IQ. These results indicate that both the choice of carcinogen as well as the dose of the tumor modulator can be important determinants of the events that occur during post-initiation exposure to CHL or I3C. Based on the present findings and data in the literature, it is possible for CHL and I3C to act as tumor promoters or anticarcinogens, depending upon the test species, initiating agent and exposure protocol.

gamma-Tubulin has been determined to be a central element of microtubule nucleation and, thus, indispensable for cellular organization of the microtubule. Utilizing the fact that human gamma-tubulin can function in the fission yeast Schizosaccharomyces pombe, we have generated a unique mutant screening procedure which can specifically select mutants of genes encoding gamma-tubulin-interacting proteins. One of the isolated mutants, cs76, turned out to carry a mutation in the alpha 1-tubulin gene (nda2(+)). This result suggests a direct interaction between the alpha- and gamma-tubulins. We located the mutation site in the nda2 gene and characterized the mutant phenotype. Our results demonstrate the importance of the alpha-/gamma-tubulin interaction in microtubule nucleation and should complement previous knowledge.

We thank Dr Heine et al1 for their interest in our recent findings2,3 and for their crucial and constructive criticisms and comments concerning the renal resistive index (RI). In response, we classified the primary composite end points into cardiovascular events, including nonfatal congestive heart failure, stroke, myocardial infarction, aortic dissection, and death, and renal events, including end-stage renal failure requiring regular hemodialysis, and found that, in a univariate Cox proportional-hazard model, a 1-SD increase of RI was a significant predictor of cardiovascular events (hazard ratio [HR], 5.47; 95% confidence interval [CI], 4.55–6.96; P

The in vitro susceptibility of methicillin-resistant Staphylococcus aureus(MRSA) to nadifloxacin and seven other fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin and sparfloxacin) was evaluated. The MRSA isolates were isolated from 114 skin infections between 1991 and 1994. Nadifloxacin exhibited the lowest minimum inhibitory concentration and there were no MRSA isolates resistant to nadifloxacin, while there were some resistant to all of the other seven fluoroquinolones. The minimum concentrations of these drugs needed to cause 50% inhibition of the isolates increased dramatically from 1991 to 1992, but has hardly changed since 1992.

Background: The action spectrum of solar urticaria varies among cases. In addition, light spectra outside the activating wavelengths can influence the wheal formation in selected patients. Objective: To know the mechanisms of light energy, we examined the effect of wavelengths on the skin and the serum factor. Methods: The patient’s skin and serum were exposed to artificial light sources, in vivo and in vitro, respectively. Results: The action spectrum ranged from UVA to visible light (∼480 nm). The exposure to longer wavelengths immediately after the exposure inhibited the development of urticaria. Conversely, the irradiation of longer wavelengths before exposure increased the wheal formation. Furthermore, UVB irradiation prior to the exposure of urticaria-eliciting light also increased the urticarial reaction, while postirradiation of UVB had no effect. The patient developed an urticarial wheal at the site of injection of her own serum, which had been previously exposed to the action spectrum in vitro. Preirradiation increased the production of the photosensitizer, while postirradiation revealed no effect. Ultrafiltration techniques showed that the molecular weight of the photosensitizer is more than 300 kD. Conclusion: We detected action, inhibition and augmentation spectra in a patient with a severe solar urticaria. Various wavelengths influence the wheal-forming factor in complex interactions.

BACKGROUND The renal resistive index (RI) measured using Doppler ultrasonography has been used as a diagnostic tool in the daily work-up of kidney diseases. A better understanding of its relationship with preclinical organ damage may help in determining overall cardiovascular risk in hypertensive patients. METHODS We evaluated the association between RI and the presence and degree of target organ damage (TOD) in 288 (130 male) essential hypertensive patients. RI, carotid intima-media thickness (IMT), and left ventricular (LV) mass index were assessed by ultrasound scan. Albuminuria was measured as the albumin-to-creatinine ratio (ACR) in three consecutive first morning urine samples. RESULTS In univariate analysis, patients with TOD showed significantly higher RI as compared with those without TOD (presence vs. absence of carotid wall thickening, LV hypertrophy, and albuminuria, P < 0.01, respectively). The severity of each TOD increased progressively from the lower to the upper RI tertile. Multiple logistic regression analysis found that each standard deviation increase in RI gave a 47% higher odds of having LV hypertrophy, and a 70% higher odds of having albuminuria (P < 0.05, respectively). The occurrence of at least two signs of TOD also significantly increased in parallel with elevation of RI (odds ratio (OR): 1.89 for 1 s.d. increase, P < 0.01). CONCLUSIONS These results suggest that increased RI may be a marker of subclinical TOD in patients with essential hypertension.

The powder-in-tube method using an Ag sheath is applied to achieve high current-capacity in the tapes of Bi-Pb-Sr-Ca-Cu-O (BPSCCO) with the high-Tc phase, by a combination of cold working and sintering. Two kinds of the BPSCCO powders with and without Ag doping are used as the materials for tape fabrication. The XRD, SEM-EDX, magnetic susceptibility and I-V characteristics at 77K obtained for above powders are presented and discussed. An improvement in Jc vs. B properties of the BPSCCO tapes by Ag doping is presented.

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Summary Endogenous gibberellins (GAs) were extracted from stems and leaves in vegetative growth stage of Gentiana triflora and identified by combined gas-chromatography/mass spectrometry and Kovats' retention indices. Five 13-hydroxylated GAs, GA 1 , GA 19 , GA 20 , GA 44 and GA 53 , were detected. The presence of GA 1 and its probable precursors GA 19 and GA 20 suggests that the early-13-hydroxylated GA biosynthetic pathway is dominant in vegetative tissues of the plant. Abundant GA 1 quantity in relative intensities suggests similarities in the GA physiology and is consistent with a common role of GA1 as a regulator of shoot growth in higher plants.

We examined 10 cases of osteochondroma by means of histopathological, histochemical and immunohistochemical techniques. The surface of the masses was covered with a cartilage tissue showing positive immunohistochemical reaction for collagen type 2, and the deep region was composed of spongy bone, showing positive immunohistochemical reaction for collagen type 1 and osteocalcin. Between the cartilage and spongy bone, which is a metaphysis-like region, a chondroidal pattern appeared in the matrix of hypertrophy cartilage. In these regions, both type 1 (and osteocalcin) and 2 collagens were immunohistochemically detected. Although there is still no direct evidence, we believe that the cells involved in so-called "chondroid bone" temporally express cartilage phenotypes and then transform directly into bone-forming cells that survive in the chondroid bone until the tissue is resorbed and remodeled. Our examination results suggest that bone formation in osteochondromas, at least in some regions, occurs through transchondroid bone formation.

The macrolide antibiotic roxithromycin is effective against acne associated with inflammation, but the mechanism by which this is achieved has not been clarified.We studied the effects of roxithromycin on the production of lipase and neutrophil chemotactic factor by Propionibacterium acnes in vitro.Roxithromycin significantly inhibited the production of lipase and neutrophil chemotactic factor by P. acnes at a concentration one eighth of the MIC, at which the growth curve of P. acnes is not affected.One mechanism of the effectiveness of roxithromycin in acne therapy is thought to be the inhibition of bacterial lipase and neutrophil chemotactic factor production by P. acnes.

Sodium-copper chlorophyllin (CHL) inhibits the formation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypt foci (ACF) and tumours in the F344 rat when it is given simultaneously with either carcinogen. However, CHL reportedly increased the incidence of dimethylhydrazine (DMH)-induced colon tumours in the same species when administered post-initiation. In the present study, rats were given IQ (130 mg/kg body weight, by oral gavages on alternating days) for 2 weeks, starting in experiment week 3, and one week after the final IQ dose rats received CHL treatment until the study was terminated at 16 weeks. Compared with animals given carcinogen alone, the mean number of IQ-induced ACF per colon was reduced significantly by 1% (w/v) CHL in the drinking water (P0.05), whereas 0.1% and 0.01% CHL had no effect. These CHL concentrations increased in a dose-related manner both the terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) and bromodeoxyuridine (BrdU) labelling indices in the distal colon. However, the lowest concentration tested, 0.001% CHL, increased the mean number of IQ-induced ACF per colon (P0.05), and increased the BrdU labelling index without a concomitant change in TUNEL. These studies indicated that 0.001% CHL promoted IQ-ACF due to deregulation of the homeostatic balance between cell birth and apoptosis in the colonic mucosa, whereas higher concentrations of CHL had either no effect or protected against IQ-induced ACF by causing dose-related increases in the overall rate of cell turnover in the colon.

Bullous pemphigoid (BP) is an autoimmune disease frequently occurring in elderly persons. It has been reported that 92-kDa gelatinase released from eosinophils cleaves the extracellular domain of BP180 protein, suggesting a direct role of eosinophils in bulla formation in this disease. The expression of the high-affinity IgE receptor, Fc epsilon RI, on eosinophils was examined in patient with BP. Samples of affected skin obtained from 7 patients with BP were stained immunohistochemically by the alkaline phosphatase anti-alkaline phosphatase (APAAP) method and mirror sections were examined. Eosinophils were present at a rate of 1.0-19.0% in lesions of the dermis, and the number of IgE-positive cells exceeded that of Fc epsilon RI-positive cells in all cases. These cells were not detected in the epidermis, and examination of mirror sections confirmed that the Fc epsilon RI-positive cells corresponded to eosinophils. It has been demonstrated that Fc epsilon RI-positive cells are involved in the dermal lesions of BP. The activation of eosinophils by Fc epsilon RI may participate in the pathogenesis of BP by triggering the degranulation of mast cells.

Chlorophyllin (CHL) is a water-soluble derivative of chlorophyll, the ubiquitous pigment in green and leafy vegetables, whereas indole-3-carbinol (I3C) is present in cruciferous vegetables such as cabbage, broccoli and cauliflower. In rats initiated with 1,2-dimethylhydrazine (DMH), CHL and I3C reportedly promoted or enhanced the incidence of colon tumors when they were administered after, or during and after the carcinogen exposure, respectively. The same compounds given post-initiation inhibited the formation of colonic aberrant crypts induced by heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), but tumor suppression was not examined in the latter studies. In the present investigation, male F344 rats were treated with IQ or DMH during the first 5 weeks of a 1 year study; IQ was given in the diet (0.03%), whereas DMH was administered once a week by s.c. injection (20 mg/kg body wt). Beginning 1 week after the last dose of IQ or DMH until sacrifice, rats received 0.001, 0.01 or 0.1% (w/v) CHL in the drinking water or 0.001, 0.01 or 0.1% I3C in the diet. Compared with controls given carcinogen alone, 0.1% I3C treatment suppressed the multiplicity of IQ-induced colon tumors, and CHL inhibited in a dose-related manner the incidence of IQ-induced liver tumors. However, 0.001% CHL increased significantly the multiplicity of DMH-induced colon tumors while having no effect on the colon tumors induced by IQ. These results indicate that both the choice of carcinogen as well as the dose of the tumor modulator can be important determinants of the events that occur during post-initiation exposure to CHL or I3C. Based on the present findings and data in the literature, it is possible for CHL and I3C to act as tumor promoters or anticarcinogens, depending upon the test species, initiating agent and exposure protocol.

Bullous pemphigoid (BP) is an autoimmune disease frequently occurring in elderly persons. It has been reported that 92-kDa gelatinase released from eosinophils cleaves the extracellular domain of BP180 protein, suggesting a direct role of eosinophils in bulla formation in this disease. The expression of the high-affinity IgE receptor, Fc epsilon RI, on eosinophils was examined in patient with BP. Samples of affected skin obtained from 7 patients with BP were stained immunohistochemically by the alkaline phosphatase anti-alkaline phosphatase (APAAP) method and mirror sections were examined. Eosinophils were present at a rate of 1.0-19.0% in lesions of the dermis, and the number of IgE-positive cells exceeded that of Fc epsilon RI-positive cells in all cases. These cells were not detected in the epidermis, and examination of mirror sections confirmed that the Fc epsilon RI-positive cells corresponded to eosinophils. It has been demonstrated that Fc epsilon RI-positive cells are involved in the dermal lesions of BP. The activation of eosinophils by Fc epsilon RI may participate in the pathogenesis of BP by triggering the degranulation of mast cells.

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.

We describe a 62-year-old Japanese woman who exhibited recurrent follicular lichenoid lesions of sarcoidosis. The skin lesions appeared all over the surface of the body without any other organ involvement, and spontaneously regressed within 1 year. Two years later, the lesions recurred on the trunk, especially in the intertriginous areas such as the submammary areas and in fatty folds of the abdomen, and on the thighs and upper arms, with the appearance of uveitis of the right eye. Histological examinations showed that small epithelioid cell granulomas were localized in the perifollicular areas. The present case was characterized by a unique distribution of follicular lichenoid eruptions, which are rare manifestations of sarcoidosis and recurrence of the lesions.

A dilemma arises in patients with chest pain or other symptoms suggestive of coronary artery disease but without significant coronary artery stenosis or spasm even after the spasm provocation test by either ergonovine or acetylcholine. Incremental doses of intracoronary acetylcholine (up to 100 micrograms for left coronary artery and 50 micrograms for right coronary artery) were administered when intravenous infusion of ergonovine 0.4 mg showed negative results. A total of 39 patients were studied. Provocation test was performed because of chest pain suggestive of coronary artery disease (n = 19), atypical chest pain (n = 6), post balloon angioplasty status (n = 6), silent ischemia (n = 4), Adams-Stokes syndrome (n = 3), and dead-on-arrival (n = 1). Characteristics of chest pain indicated variant angina (n = 11), rest angina (n = 4), and effort angina (n = 4). No electrocardiographic evidence of ischemia was detected before this test in any patient. Spasm was induced in 23 patients (59.0%) with complete obstruction in 7 (30.4%), diffuse vasoconstriction (90-99%) in 14 (60.9%), and focal spasm in 2 (8.7%). The patients with chest pain showed the highest positive rate of 78.9%. Further, the patients with atypical chest pain and miscellaneous reasons also revealed positive rates of 33.3% and 42.9%, respectively. One ventricular tachycardia and 2 atrial fibrillations occurred but terminated spontaneously. This test is useful for detecting spasm in a variety of patients in whom intravenous ergonovine infusion fails to induce spasm.

gamma-Tubulin is a member of the tubulin superfamily and plays essential roles in microtubule nucleation. While the level of other tubulins, alpha- and beta-tubulin, is strictly regulated in higher eukaryotes and overexpression of beta-tubulin is toxic in yeasts, gamma-tubulin can be overexpressed by fivefold in fission yeast without any obvious defect in growth. Extreme overexpression of gamma-tubulin in mammalian cells caused growth arrest; however, the exact level of gamma-tubulin and the critical level of gamma-tubulin necessary for growth defect were undetermined. We have constructed strains that over- or underexpress gamma-tubulin by placing the gamma-tubulin gene under the control of the inducible nmt1 promoter and its variants. Among these, the weakest promoter was able to produce enough gamma-tubulin to support normal growth when its expression was induced. A strain in which the gamma-tubulin gene was placed under the control of the strongest inducible promoter achieved 160-fold overexpression of gamma-tubulin and its growth was suppressed. Normal cytoplasmic microtubules were mostly lost in gamma-tubulin overexpressing cells and gamma-tubulin was accumulated around the periphery of nuclei. Many of the cells were arrested in mitosis. A small fraction of cells did proceed to undergo nuclear division; however, its process looked either significantly deterred or abnormal. Our results presented here suggest that excess gamma-tubulin disrupts the microtubule array and significantly deters the formation of the mitotic spindle, most likely because of random nucleation of microtubules from excess gamma-tubulin in the cytoplasm.

The present study investigated the secretion level and gene expression of adrenomedullin (AM), a novel vasorelaxant peptide, in cultured neonatal rat cardiac myocytes and nonmyocytes, and the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) on its production and secretion in these cells. Under serum-free conditions, both myocytes and nonmyocytes secreted immunoreactive (ir-) AM into the culture medium in a time-dependent manner. The secretion rates of ir-AM from myocytes and nonmyocytes per 10(5) cells were almost equivalent. The expression of AM messenger RNA was also observed in cultured myocytes and nonmyocytes. The peptide secretion and messenger RNA level of AM in cardiac myocytes were increased after stimulation with IL-1beta. In nonmyocytes, IL-1beta and TNF alpha remarkably augmented both the release of ir-AM into the medium and AM gene expression after 24 and 48 h of incubation. These observations indicate that cardiac ventricular cells (i.e. myocytes and nonmyocytes) actively produce AM and also suggest that cytokines such as IL-1beta and TNF alpha regulate the gene expression and secretion of this peptide in the ventricles. On the basis of these results and the findings that IL-1beta and TNF alpha are involved in heart failure and cardiac hypertrophy, AM may play a role as an autocrine/paracrine modulator in some cardiac disorders.

Expression of CD45RB on CD4+ or CD8+ cells in combination with TCRV beta usages (V beta 6, V beta 8.1, V beta 8.2, V beta 11 and V beta 17a) in normal mouse strains (BALD/c and C57BL/6) was compared with autoimmune-prone strains (NZW x BXSB) F1 and MRL/lpr) at young and old ages. The frequencies, and also the numbers of CD45RB- cells in CD4+ T cells with various TcR repertoires was significantly less in the autoimmune-prone stains at old ages, while, in normal control strains, they remained unchanged. Furthermore, CD4+/CD45RB- cells are CD44high and CD62L (L- selectin).low These findings suggest that most T cells, especially CD4+ T cells, in old W/BF1 and old MRL/lpr mice, were activated and this may reflect the elevation of autoantibodies and the progress of autoimmune status in aged autoimmune-prone mice. This will be discussed in relation to the progress of the autoimmune diseases.