Visit-to-visit blood pressure variability, average BP level and carotid arterial stiffness in the elderly: a prospective study.

In a cross-sectional study, visit-to-visit blood pressure (BP) variability was shown to be associated with artery remodelling. Here, we investigated the impact of visit-to-visit BP variability and average BP on the carotid artery remodelling progression in high-risk elderly according to different classes of antihypertension medication use/non-use. BP measurements and carotid ultrasound were performed in the common carotid artery in 164 subjects (mean age 79.7 years at baseline, 74.7% females) with one or more cardiovascular risk factors. Based on 12 visits (1 × /month for 1 year), we calculated visit-to-visit BP variability expressed as the standard deviation (s.d.), coefficient of variation (CV), maximum BP, minimum BP and delta (maximum-minimum) BP. We measured mean intima-media thickness (IMT) as well as stiffness parameter ß were measured at baseline and at the mean 4.2-year follow-up. In a multiple regression analysis, the maximum, minimum, s.d. and average of systolic BP (SBP) were significantly associated with a change in ß-values between the baseline and follow-up after adjustment for age, smoking, lower high-density lipoprotein level, baseline ß-value and follow-up period. There were no significant associations between the visit-to-visit BP variability measures and the change in mean IMT. Significant associations of maximum, minimum, s.d. and average SBP were found with increased ß-values in the subjects without calcium channel blocker (CCB) use and in the subjects using renin-angiotensin system inhibitors (RASIs). Thus, exaggerated visit-to-visit SBP variability and a high average SBP level were significant predictors of progression in carotid arterial stiffness in high-risk elderly without CCBs use and in those using a RASI.

Prospective study comparing the new sclerotherapy and hemorrhoidectomy in terms of therapeutic outcomes at 4 years after the treatment.

PURPOSE: Recently, sclerotherapy using a new sclerosing agent (aluminum potassium sulfate and tannic acid) has become widespread in Japan as a treatment for hemorrhoids. In the present study, we investigated whether sclerotherapy or surgical therapy (hemorrhoidectomy) is superior in terms of the therapeutic outcomes at 4 years. METHODS: We sent a questionnaire on symptoms and the degree of satisfaction to patients who underwent sclerotherapy or hemorrhoidectomy for grade 3 or 4 hemorrhoids in 2007, and compared the two therapies based on the responses, with respect to superiority of the therapeutic outcomes at 4 years. To identify the factors affecting the symptom-free and satisfaction rates, the univariate and multivariate analyses were performed for the following seven parameters: age, sex, degree of hemorrhoids, presence of external hemorrhoids, past history of treatment for hemorrhoids, number of hemorrhoids treated and the type of treatment. RESULTS: Overall, 75 % of the patients (195/260) responded to the questionnaire. In this study, the symptom-free rates were 53 % (30/57 patients) in the sclerotherapy group and 80 % (111/138 patients) in the hemorrhoidectomy group, and the satisfaction rates were 70 % (40/57 patients) in the sclerotherapy group and 88 % (121/138 patients) in the hemorrhoidectomy group. The results revealed that the type of treatment was the only factor affecting these two outcomes. CONCLUSIONS: Our results indicate that hemorrhoidectomy is superior to sclerotherapy. These findings may be useful in the treatment of hemorrhoid patients.

Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam.

1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.

Toxicity test using medaka (Oryzias latipes) early fry and concentrated sample water as an index of aquatic habitat condition.

The aim of the present study was to show a relationship between toxicity of 100-fold concentrated water and aquatic habitat conditions. Environmental waters are 100-fold concentrated with solid-phase extraction. Medaka early fry was exposed in these waters for 48 h. The number of death and disorder was counted at 1, 2, 3, 6, 12, 24, and 48 h; toxicity was expressed using inverse median effect time and median lethal time (ET (50)(-1), LT (50)(-1)). Average score per taxon (ASPT) for benthic animals and Index of Biotic Integrity (IBI) for fish were applied as indices of aquatic habitat conditions. The results of toxicity test were compared using ASPT and IBI. The different levels of toxicity were detected in the seawater of Japan. At the Husino River area, toxicity cannot be detected. In rivers, high toxicity appeared at urban districts without sewerage. By Spearman coefficient, the relationship between toxicity and high biochemical oxygen demand (BOD) were obtained. BOD household wastewater contains hydrophobic toxic matters; otherwise, seawater in industrial area does not show clear relationship between toxicity and chemical oxygen demand. Gas chromatography to mass spectrometry simultaneous analysis database may give an answer for the source of toxicity, but further test is required. Ratio of clear stream benthic animal sharply decreased over 0.25 of LT (50)(-1) or 0.5 of ET (50)(-1). Tolerant fish becomes dominant over 0.3 of LT (50)(-1) or 0.5-1.0 of ET (50)(-1). By Pearson product-moment correlation coefficient, correlation coefficient between toxicity and ASPT was obtained at -0.773 (ET (50)(-1)) and -0.742 (LT (50)(-1)) at 1 % level of significance with a high negative correlation. Toxicity (LT (50)(-1) ) has strong correlation with the ratio of tolerant species. By Pearson product-moment correlation coefficient, correlation coefficient between toxicity and IBI obtained were -0.155 (ET (50)(-1)) and -0.190 (LT (50)(-1)) at 1 % level of significance and has a low or no correlation between toxicity and IBI. Even with low toxic environmental waters, toxicity test using 100-fold concentrated and medaka early fly could detect acute toxicity. The detected toxicity seemed to limit the inhabiting aquatic species in the water body.

Common occurrence of everolimus-associated aphthous stomatitis in Japanese heart transplant recipients.

Mammalian target of rapamycin (mTOR) inhibitors display antiproliferative effects with less nephrotoxicity than calcineurin inhibitors. However, clinical use of mTOR inhibitors can be associated with a series of adverse events. We experienced cases of aphthous stomatitis associated with everolimus (EVL) in four Japanese heart transplant recipients treated at the target trough EVL blood level after a switch from mycophenolate mofetil between April and December 2007. All four patients developed aphthous stomatitis; three required reduction of the exposure and one, EVL discontinuation due to stomatitis as well as other side effects. All patients recovered from stomatitis after reduction or withdrawal of EVL. Thus, we considered that EVL-related stomatitis might occur commonly among the Japanese population. The proper dosage, effects, and frequency of the side effects of mTOR inhibitors may vary by ethnic population.

Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma.

BACKGROUND: Tiotropium bromide, a long acting muscarinic receptor inhibitor, is a potent agent for patients with bronchial asthma as well as chronic obstructive pulmonary disease. OBJECTIVE: The aim of this study was to evaluate whether tiotropium bromide can inhibit allergen-induced acute and chronic airway inflammation, T helper (Th)2 cytokine production, and airway remodelling in a murine model of asthma. METHODS: Balb/c mice were sensitized and challenged acutely or chronically to ovalbumin (OVA). The impact of tiotropium bromide was assessed using these mice models by histologic, morphometric, and molecular techniques. Moreover, the effect of tiotropium bromide on Th2 cytokine production from purified human peripheral blood mononuclear cells (PBMCs) was assessed. RESULTS: Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma. The levels of TGF-beta1 were also reduced by tiotropium bromide in BALF in a chronic model. The goblet cell metaplasia, thickness of airway smooth muscle, and airway fibrosis were all significantly decreased in tiotropium bromide-treated mice. Moreover, airway hyperresponsiveness (AHR) to serotonin was significantly abrogated by tiotropium bromide in a chronic model. Th2 cytokine production from spleen cells isolated from OVA-sensitized mice was also significantly inhibited by tiotropium bromide and 4-diphenylacetoxy-N-methylpiperidine methiodide, which is a selective antagonist to the M3 receptor. Finally, treatment with tiotropium bromide inhibited the Th2 cytokine production from PBMCs. CONCLUSION: These results indicate that tiotropium bromide can inhibit Th2 cytokine production and airway inflammation, and thus may reduce airway remodelling and AHR in a murine model of asthma.

Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome.

The aim of this study was to determine whether a relatively low dose of pioglitazone or metformin was effective in diabetic patients with metabolic syndrome. Fifty diabetic patients with metabolic syndrome were randomly assigned to a low-dose pioglitazone (15 mg/day) treatment group or a low-dose metformin (500 mg/day) treatment group. Drugs were administered for 12 weeks. Systolic and diastolic blood pressure, heart rate, body mass index, triglyceride (TG), HDL and LDL-cholesterol, fasting plasma glucose (FPG), fasting plasma insulin (IRI), postprandial glucose, and HOMA-IR in the 75gOGTT, HbA1c, high-sensitivity CRP (hs-CRP) determined by cervical artery echography, and pulse wave velocity (PWV) were measured before/after 12-week drug administration. Significant decreases in HbA1c and HOMA-IR were noted in the pioglitazone group, along with significant decreases in TG, AST, ALT, blood pressure, hs-CRP and PWV. Significant decreases in HbA1c, HOMA-IR, BMI and waist circumference were noted in the metformin group. The pioglitazone group significantly improved the values for ALT, systolic blood pressure, hs-CRP and PWV compared to the metformin group. However, the metformin group demonstrated significant improvement in BMI compared with the pioglitazone group. Using a low dose regimen, pioglitazone significantly improved blood pressure and hepatic function and may be more effective than metformin to reduce risk factors in Japanese diabetic patients with metabolic syndrome at preventing atherosclerosis.

Which factors predict the recovery of natural heart function after insertion of a left ventricular assist system?

BACKGROUND: Recent reports have demonstrated that use of a left ventricular assist system (LVAS) can initiate recovery of cardiac function, and subsequent weaning from the LVAS has attracted considerable interest. In this study we investigated reliable predictors of LVAS weaning. METHODS: Eighty-two patients underwent LVAS implantation between April 1994 and July 2006 at our institution. Cardiac function was restored in 8 patients, who were weaned from LVAS after a mean of 5 months (Group R). Thirty-three patients remained on LVAS support for >1 year (Group N) because natural heart function did not show adequate improvement. We retrospectively evaluated the differences between these two groups. Group R was younger, and had a shorter duration of heart failure than Group N (23.4 vs 36.7 years and 13.3 vs 56.1 months, p < 0.01, respectively). Pathologic findings showed that the interstitial fibrosis score was lower in Group R (p < 0.01). Three months after LVAS insertion, B-type natriuretic peptide (BNP) and fractional shortening (FS) were more favorable (66.6 +/- 46 vs 264.5 +/- 170 pg/ml, p < 0.01, and 23 +/- 17.1 vs 12 +/- 9.1%, p < 0.05, respectively) in Group R. Furthermore, Group R received a higher dose of beta-blocker (15.4 +/- 8.4 vs 5.8 +/- 3.9 mg, p < 0.05). CONCLUSIONS: Younger age, shorter history of heart failure, and less interstitial fibrosis were effective predictors of weaning from LVAS. Restoration of natural heart function was more rapid and more persistent in candidates for LVAS explantation, and presence of beta-blocker played a prominent role in improving cardiac function after LVAS implantation.

Heterogeneity of regional systolic function detected by tissue Doppler imaging is linked to impaired global left ventricular relaxation in hypertrophic cardiomyopathy.

OBJECTIVE: To evaluate regional and global left ventricular (LV) function and LV wall thickness (LVWT) in patients with hypertrophic cardiomyopathy (HCM). DESIGN AND SETTING: Observational study at the National Cardiovascular Centre and Nagoya University Hospital in Japan. PARTICIPANTS: Thirty-six patients with HCM and 16 patients with hypertensive LV hypertrophy (LVH). MAIN OUTCOME MEASURES: Conventional echocardiography and strain rate (SR) imaging derived from tissue Doppler imaging were performed. Systolic strain (epsilon(sys)), peak systolic SR (SR(sys)), peak early diastolic SR (SR(dia)) and LVWT were obtained from eight LV segments. LV pressure was simultaneously recorded with a high-fidelity micromanometer. RESULTS: The regional epsilon(sys) and SR(sys) were correlated with LVWT in patients with HCM (r = 0.50, p<0.001 and r = 0.63, p<0.001, respectively) but not in patients with hypertensive LVH. The standard deviations of LVWT, epsilon(sys) and SR(sys) obtained from the eight LV segments of each subject were greater for patients with HCM than for patients with hypertensive LVH. The standard deviation of LVWT was correlated with those of epsilon(sys) and SR(sys) (r = 0.55, p<0.001 and r = 0.56, p<0.001, respectively). The standard deviations of LVWT, epsilon(sys) and SR(sys) were correlated with tau (r = 0.35, p<0.05; r = 0.47, p<0.001; and r = 0.39, p<0.005, respectively). CONCLUSIONS: Heterogeneity of regional LV systolic function detected by SR imaging is in part attributable to heterogeneity of LVH and may be linked to impaired global LV relaxation in HCM.

Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B.

AIMS: A rare case of the insulin autoimmune syndrome (IAS) accompanied by insulin receptor anomaly is reported. METHODS: Antibodies to insulin and insulin receptor were determined in the patient with severe hypoglycaemia before and after the treatment with prednisolone. RESULTS: Titers of antibody to insulin and insulin receptors were 73.0% and 41.5%, respectively. Drug-induced lymphocyte stimulation tests were all negative for the suspicious drugs. Her HLA-DR was DRB1*0403/04051. Following steroid therapy, the formation of antibodies was suppressed and alleviated her symptoms. Scatchard analysis yielded findings specific to polyclonal antibodies. CONCLUSIONS: The changes in autoantibodies resulted in alleviation of the hypoglycemic symptoms as a result of steroid therapy.

A cone-beam volume CT using a 3D angiography system with a flat panel detector of direct conversion type: usefulness for superselective intra-arterial chemotherapy for head and neck tumors.

BACKGROUND AND PURPOSE: The development of flat panel detectors (FPDs) has made cone-beam CT feasible for practical use in a clinical setting. Our purpose was to assess the usefulness of cone-beam CT using the FPD in conjunction with conventional digital subtraction angiography (DSA) for performing superselective intra-arterial chemotherapy for head and neck tumors. MATERIALS AND METHODS: Twenty-three consecutive patients (43 feeding arteries) were prospectively examined. All of the patients underwent intra-arterial rotational angiography using an FPD system, and the cone-beam CT was reconstructed from the volume dataset. Two radiologists evaluated the quality of the cone-beam CT and then evaluated whether the additional information provided by the cone-beam CT was useful for the interventional procedures. RESULTS: In 41 (95%) of 43 arteries, the extent of contrast material perfusion was sufficiently visualized on cone-beam CT. In 20 (47%) of 43 arteries, the DSA plus cone-beam CT was superior to the DSA alone regarding the precise understanding of vascular territory of each artery. This information was helpful for predicting the drug delivery for superselective intra-arterial chemotherapy, especially in deeply invasive tumors with multiple feeding arteries. CONCLUSION: In superselective intra-arterial chemotherapy for head and neck tumors, cone-beam CT with FPD provides useful additional information, which allows interventional radiologists to determine the feeders, as well as the dose of antitumor agent for each feeder.

Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte-derived dendritic cells from patients with asthma.

BACKGROUND: Dendritic cells (DCs) are antigen-presenting cells that efficiently activate T cells. OBJECTIVE: We examined the effects of suplatast tosilate, which prevents T-helper type 2 responses, on the differentiation and function of monocyte-derived DCs (moDCs). METHODS: DCs were differentiated in vitro from peripheral monocytes from patients with asthma by the addition of granulocyte macrophage colony-stimulating factor and IL-4 in the presence or absence of suplatast tosilate. Cell surface molecules (CD1a, CD14, CD80, CD83, CD86, HLA-DR) on immature and mature DCs were analysed with flow cytometry, and the secretion of CC chemokine ligand (CCL)17 (thymus and activation-regulated chemokine), IL-12p70, IL-12p40, and IL-10 was measured with an ELISA. We also studied the proliferative responses of allogeneic CD4(+) T cells from healthy subjects to DCs differentiated in the presence of suplatast tosilate. In addition, the production of IFN-gamma and IL-5 by CD4(+) T cells after coculture with untreated DCs or suplatast tosilate-treated DCs was measured with ELISA. RESULTS: Suplatast tosilate significantly inhibited the expression of CD1a, CD80, and CD86 on immature DCs and of CD1a, CD80, CD83, and CD86 on mature DCs. Suplatast tosilate also significantly inhibited the secretion of CCL17, IL-12p70, and IL-12p40; however, the secretion of IL-10 was not affected. The proliferative responses of allogeneic CD4(+) T cells to suplatast tosilate-treated DCs were suppressed. Moreover, suplatast tosilate-treated DCs had an impaired capacity to stimulate CD4(+) T cells to produce IFN-gamma and IL-5. CONCLUSION: Suplatast tosilate inhibits the differentiation, maturation, and function of moDCs.

3D digital subtraction angiography of intracranial aneurysms: comparison of flat panel detector with conventional image intensifier TV system using a vascular phantom.

BACKGROUND AND PURPOSE: Compared with the image intensifier (I.I.)-TV system, the flat panel detector (FPD) system of direct conversion type has several theoretic advantages, such as higher spatial resolution, wide dynamic range, and no image distortion. The purpose of this study was to compare the image quality of 3D digital subtraction angiography (DSA) in the FPD and conventional I.I.-TV systems using a vascular phantom. MATERIALS AND METHODS: An anthropomorphic vascular phantom was designed to simulate the various intracranial aneurysms with aneurysmal bleb. The tubes of this vascular phantom were filled with 2 concentrations of contrast material (300 and 150 mg I/mL), and we obtained 3D DSA using the FPD and I.I.-TV systems. First, 2 blinded radiologists compared the volume-rendering images for 3D DSA on the FPD and I.I.-TV systems, looking for pseudostenosis artifacts. Then, 2 other radiologists independently evaluated both systems for the depiction of the simulated aneurysm and aneurysmal bleb using a 5-point scale. RESULTS: For the degree of the pseudostenosis artifacts at the M1 segment of the middle cerebral artery at 300 mg I/mL, 3D DSA with FPD system showed mild stenoses, whereas severe stenoses were observed at 3D DSA with I.I.-TV system. At both concentrations, the FPD system was significantly superior to I.I.-TV system regarding the depiction of aneurysm and aneurysmal bleb. CONCLUSION: Compared with the I.I.-TV system, the FPD system could create high-resolution 3D DSA combined with a reduction of the pseudostenosis artifacts.

Reduction of radiation dose for cerebral angiography using flat panel detector of direct conversion type: a vascular phantom study.

BACKGROUND AND PURPOSE: Compared with image intensifier television (I.I.-TV) system, an angiography system using the flat panel detector (FPD) of direct conversion type has a high spatial resolution, which may improve image quality, reduce patient exposure, or both. Our purpose was to evaluate the detection of simulated aneurysmal blebs under dose reduction with the FPD system in comparison with the I.I.-TV system. MATERIALS AND METHODS: A vascular phantom was designed to simulate various intracranial aneurysms with and without blebs, and this phantom was filled with 3 different concentrations of contrast material (300, 150, and 100 mg I/mL). 2D digital subtraction angiography (DSA) at low-dose mode of FPD system was compared with 2D DSA at a standard-dose mode of FPD system and a conventional mode of I.I.-TV system. Data analysis was based on 171 observations (57 aneurysms [20 with bleb and 37 without bleb] x 3 contrast material concentrations) by each of 7 radiologists, and the detection performances of blebs were compared using a receiver operating characteristic (ROC) analysis. RESULTS: The mean dose measurements with a phantom during 2D DSA were 0.36 mGy/frame with low-dose mode of FPD system, 0.72 mGy/frame with standard-dose mode of FPD system and 0.76 mGy/frame with I.I.-TV system. The mean Az at 100 mg I/mL was significantly higher for low-dose mode of FPD than for conventional-dose mode of I.I.-TV mean Az, 0.85 versus 0.56; P < .01), though differences were not significant with 150 and 300 mg I/mL between both systems. CONCLUSION: The FPD system allows a considerable dose reduction during 2D DSA without loss of the image quality.