Uric acid levels predict future blood pressure and new onset hypertension in the general Japanese population.

We tested the hypothesis that uric acid levels predict new-onset hypertension in the Japanese general population. Normotensive individuals who visited our hospital for a yearly health checkup (n=8157, men=61.0% and age=50.7±12.2 years) were enrolled in the present study. After baseline evaluation, participants were followed up for a median of 48.3 months (range 4.9-101.0 months), with the endpoint being the development of hypertension, defined as systolic blood pressure (BP) > or = 140 mm Hg, diastolic BP > or = 90 mm Hg or the use of antihypertensive medication. The impact of uric acid and other cardiovascular risk factors at baseline on future BP and development of hypertension was assessed. During follow-up, 19.0% of women (n=605) and 29.5% of men (n=1469) participants developed hypertension. Incident hypertension was increased across the quartiles for baseline uric acid levels (P<0.0001), and multivariate Cox proportional hazards analysis revealed a significant and independent association between the uric acid level and the onset of hypertension in both men and women participants (P<0.05). Furthermore, uric acid was independently and positively correlated with future BP (P<0.05). Thus, uric acid is an independent predictor of new-onset hypertension in both women and men.

A randomized multicenter phase II trial on the efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma.

BACKGROUND: The purpose of this study was to investigate the usefulness of a hydrocolloid dressing containing ceramide for hand-foot skin reaction (HFSR) on the soles of the feet in metastatic renal cell carcinoma (RCC) patients treated with sorafenib. PATIENTS AND METHODS: Patients with grade 1 HFSR on the soles of the feet were randomly assigned in to two groups. One group received a hydrocolloid dressing containing ceramide (arm A) and the other received 10% urea cream (arm B). Patients in both groups applied treatment to the affected sites on the soles of the feet, but not to the hands. The primary end point was the incidence of grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks. RESULTS: Thirty-three patients were assessed (17 in arm A and 16 in arm B), and there were no significant differences in baseline characteristics between the two groups. During the observation period of this study, grade 2 or 3 HFSR on the soles of the feet was found in 29% of patients in arm A and was significantly less than the 69% in arm B (P=0.03). The incidence of HFSR on the hands, however, was similar in both arms. The median time to grade 2 or 3 HFSR on the soles of the feet was also significantly longer in arm A than in arm B (P=0.03). CONCLUSIONS: These results indicate that a hydrocolloid dressing containing ceramide prevented the worsening of HFSR caused by sorafenib in metastatic RCC patients. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002016.

Factors associated with brachial-ankle pulse wave velocity in the general population.

The present study investigated factors that modify or affect arterial stiffness as assessed by brachial-ankle pulse wave velocity (baPWV) in the general population. Subjects had previously participated in a physical checkup program (n=911), and baPWV and urinary albumin and sodium excretion were also measured. Urine albumin was expressed as the ratio of urine albumin to urine creatinine. Individual salt intake was assessed by estimating 24-h urinary salt excretion and expressed as the ratio of estimated salt intake to body weight. The mean blood pressure and baPWV were 127.1±15.2/77.0±9.5 mm Hg and 15.9±3.3 m s(-1), respectively. Univariate analysis demonstrated that baPWV correlated with various factors including age, blood pressure, electrocardiogram voltage (SV(1)+RV(5)), urine albumin and salt intake. Multivariate regression analysis revealed that electrocardiogram voltage (P<0.001), systolic blood pressure (P<0.0001), urine albumin (P<0.001) and salt intake (P<0.001), independently correlated with baPWV after adjustment for other possible factors. Similar results were obtained for participants not taking any medication. These results suggest that the baPWV value is independently associated with individual salt intake and cardiac and renal damage, and could be a useful procedure for identifying individuals with concealed risk of cardiovascular disease.

Effects of up-titration of candesartan versus candesartan plus amlodipine on kidney function in type 2 diabetic patients with albuminuria.

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (≥30 mg g(-1) creatinine) were enroled in the study, and were either started on or switched to candesartan (8 mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP ≥130/80 mm Hg were randomly assigned to receive either candesartan (12 mg per day) or candesartan (8 mg per day) plus amlodipine (2.5 mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (-40±14% vs -9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction.

PR3-ANCA-positive crescentic necrotizing glomerulonephritis accompanied by isolated pulmonic valve infective endocarditis, with reference to previous reports of renal pathology.

Patients with infective endocarditis (IE) often have renal complications which may include infarcts, abscesses and glomerulonephritis (GN). Furthermore, it is generally accepted that there is an association between IE and anti-neutrophil cytoplasmic antibody (ANCA). Here, we report the case of a 24-year-old man who developed rapidly progressive GN in the course of IE due to infection with alpha-streptococcus. The initial clinical manifestation of the condition was severe sacroiliitis without fever. Sandwich ELISA showed that the patient was positive for PR3-ANCA at low titer, and the classical complement pathway was also activated. Renal biopsy demonstrated several lesions: focal embolic GN, GN with immune deposits and focal and segmental crescentic necrotizing GN. Treatment with antibiotics and steroids led to eradication of the infection, and resolution of the renal disease was accompanied by immediate disappearance of PR3-ANCA and hypocomplementemia. During a 4-year follow-up period, no recurrence was observed. There have only been 7 case reports of GN associated with IE and PR3-ANCA in which the renal pathology has been described, and the current report is the first to document renal pathology in a patient with isolated pulmonic valve IE and PR3-ANCA. Moreover, this report is the first to show a change in renal biopsy findings in response to treatment. A review of the 7 literature cases and that of our patient showed that none involved pauci-immune GN. Hence, further studies are needed to clarify the prevalence of pauci-immune GN in ANCA-positive IE patients.

Immunotactoid glomerulopathy with microtubular deposits, with reference to the characteristics of Japanese cases.

We present the case of a 69-year-old man with nephrotic syndrome and renal insufficiency, who developed lobular glomerulonephritis. An electron microscopy examination of a renal biopsy showed microtubular structures of 24 nm in diameter in the subendothelial space and the paramesangial area. These deposits were PAS-positive and Congo red-negative, and revealed predominantly positive staining for kappa light chain. There was no evidence of diseases with highly organized glomerular deposits, such as amyloidosis, cryoglobulinemia, systemic lupus erythematosus or paraproteinemia. Therefore, the patient was diagnosed to have immunotactoid glomerulopathy (ITG). During a seven-year course he has not developed any disease known to be associated with organized glomerular immune deposits. Hence, we believe ITG occurred as a primary glomerular disease in this case. We also highlight cases of ITG with microtubular deposits that have been reported in Japan, compare these cases to previous reports, and show that the characteristics of the Japanese cases are male predominance; a high incidence of membranoproliferative glomerulonephritis (MPGN); a low incidence of monoclonal gammopathy and hematological malignancies and a higher incidence of hypocomplementemia.

Cyclooxygenase-2 expression and relationship to tumour progression in human renal cell carcinoma.

AIMS: Cyclooxygenase (COX), which catalyses the synthesis of prostaglandins from arachidonic acid, has two isoforms; COX-1 and COX-2. There is ample evidence to suggest an important role for COX-2 in cancer. The aim of this study was to evaluate the clinical significance of COX-2 expression and its localization in the development and progression of human renal cell carcinoma (RCC). METHODS AND RESULTS: The expression and localization of COX-2 were evaluated in human RCC tissues from 75 patients by immunohistochemistry. Immunoreactive COX-2 protein was observed in all cases of RCC, and the levels of COX-2 expression were correlated with tumour grade and pathological stage. Expression of COX-2 was higher in the granular cell subtype than in the clear cell subtype of RCC. Immunoelectron microscopy revealed that COX-2 was expressed in the nuclear membrane, rough endoplasmic reticulum, Golgi complex and mitochondrial membrane of RCC cells. CONCLUSION: COX-2 overexpression within these intracellular organelles in RCC may be associated with renal cell carcinogenesis and COX-2 may be a useful biomarker in RCC.

Striking effect of left ventricular high filling pressure with mitral regurgitation on mitral annular velocity during early diastole. A study using colour M-mode tissue Doppler imaging.

AIMS: To evaluate the effect of considerably high left ventricular filling pressure with mitral regurgitation on mitral annular velocity during early diastole. SUBJECTS: Two hundred and forty-three patients who underwent cardiac catheterization for evaluation of chest pain. METHODS: Mitral annular velocity during early diastole was measured by colour M-mode tissue Doppler imaging. Patients were divided into the following three groups according to the cardiac catheterization data. Group A (n=147): patients having left ventricular relaxation time constant tau<46 ms and left ventricular end-systolic volume index <38 ml m(-2); group B (n=88): patients having tau>or=46 ms and/or end-systolic volume index >or=38 ml m(-2); group C (n=8): patients having mean pulmonary capillary wedge pressure >or=16 mmHg in addition to tau>or=46 ms and end-systolic volume index >or=38 ml m(-2). RESULTS: Mitral annular velocity during early diastole was significantly less in group B (4.8+/-1.4 cm s(-1)) than in group A (7.7+/-1.9 cm s(-1)). However, there was no significant difference between groups A and C (8.3+/-0.8 cm s(-1)). A transmitral E/A >1.0 was observed in 12/147 patients of group A, 10/88 of group B, and 8/8 of group C. The incidence of >or=Sellers' grade II mitral regurgitation was higher in group C than the others. CONCLUSIONS: A paradoxically faster mitral annular velocity during early diastole is found in patients having left ventricular dysfunction with moderate to severe mitral regurgitation and considerably high left ventricular filling pressure. Attention should be paid to an interpretation of mitral annular velocity during early diastole regarding left ventricular early diastolic performance in patients having mitral regurgitation with an E/A >1.0 in their transmitral flow.

Postural response of low-frequency component of heart rate variability is an increased risk for mortality in patients with coronary artery disease.

STUDY OBJECTIVES: We examined whether autonomic functions assessed by heart rate variability (HRV) during standardized head-up tilt testing (HUTT) predict risk for death in stable patients with coronary artery disease (CAD). DESIGN AND SETTING: Retrospective cohort study in medium-sized university general hospital. MEASUREMENTS AND RESULTS: In a cohort of 250 patients with CAD who were undergoing elective coronary angiography, we analyzed HRV during standardized HUTT under paced breathing with discontinuation of treatment with all medications. During a subsequent mean follow-up period of 99 months, there were 13 cardiac deaths and 12 noncardiac deaths. Cox regression analysis adjusted for cardiovascular risks revealed that increased postural change (supine to upright) in the power of low-frequency component (LF) power predicted an increased risk for cardiac death (relative risk [per 1-ln ms(2) increment], 4.36; 95% confidence interval, 1.64 to 11.6), while neither the high-frequency component nor its response to HUTT predicted any form of death. When the patients were trichotomized by the level of postural LF change (large drop, < or = - 0.6 ln[ms(2)]; small drop and rise, > 0 ln[ms(2)]), the three groups did not differ in terms of clinical features or CAD severity at baseline or coronary interventions during the follow-up period; however, the 8-year cardiac mortality rates were 0%, 6%, and 12%, respectively (p = 0.008 [log rank test]). Additionally, the difference was enhanced when analyzed excluding 64 patients who had been treated with a beta-blocker during the follow-up period (0%, 7%, and 15%, respectively; p = 0.006 [log rank test]). CONCLUSIONS: The postural response of HRV predicts the risk for death in patients with CAD. Postural LF increase (LF rise), in particular, is an independent risk factor for cardiac death.

Reversion of temperature-sensitive mutation by inhibition of proteasome-mediated degradation of mutated D123 protein.

A temperature-sensitive cell-cycle mutant of the 3Y1 rat fibroblast cell line, 3Y1tsD123 has in the D123 gene coding region a point mutation which causes instability of the D123 protein. Temperature-sensitive G1 arrest of the mutant is caused by increased degradation of the D123 protein at restrictive temperature. In this study we found that the selective proteasome inhibitors lactacystin and MG132 inhibited degradation of the mutated D123 protein in cell lines overexpressing the mutated D123 protein, followed by accumulation of a modified form (increased molecular weight other than by ubiquitination) of the D123 protein. Although a temperature-resistant revertant of the mutant had no further mutation in the D123 gene coding region, the modification of the mutated D123 protein was inhibited and the mutated D123 protein was rendered stable. The modification was also inhibited in the hybrid cell lines between the revertant and the cell line overexpressing the mutated D123 protein. These facts imply that the mutated D123 protein receives unidentified modification before degradation in the proteasome, and that the revertant expresses a gene inhibiting this modification.

Striking effect of left ventricular systolic performance on propagation velocity of left ventricular early diastolic filling flow.

Propagation velocity of left ventricular (LV) early diastolic filling flow (PVE) has been acknowledged as a useful parameter for LV early diastolic performance; however, the effect of LV systolic performance on PVE is not fully understood. Thus the purpose of this study was to investigate such an effect. Propagation of LV early diastolic filling flow was visualized by M-mode color Doppler imaging, and the slopes of the peak velocity tracings were measured as PVE in 150 patients who underwent coronary angiography. In cardiac catheterization, mean pulmonary capillary wedge pressure, time constant tau of LV pressure decay, LV end-systolic volume index, and LV ejection fraction were obtained. In univariate regression analysis, PVE significantly correlated with LV end-systolic volume index (r = -0.68, P <.001), LV ejection fraction (r = 0.66, P <.001), and time constant tau (r = -0.52, P <.001). In multivariate regression analysis, PVE was regressed by the LV end-systolic volume index, tau, and mean pulmonary capillary wedge pressure. The contribution of each parameter to the variance of the PVE was 46%, 3%, and 2%, respectively. A break-point linear regression analysis showed that the relation between the LV end-systolic volume index and PVE was much better characterized by a broken line than a straight line. The broken line had a steeper slope in patients with LV end-systolic volume index < or =41 mL/m(2) than in those with >41 mL/m(2). These findings suggest that PVE is determined mainly by LV systolic performance and partly by both LV relaxation and LV filling pressure. Left ventricular systolic performance may play a key role in generating a much faster PVE, especially in patients with relatively better LV systolic performance.

Cholesteryl ester transfer protein deficiency causes slow egg embryonation of Schistosoma japonicum.

In our attempt to discover a potential cause for accumulation of cholesteryl ester transfer protein (CETP) deficiency in Eastern Asia, we studied the association of CETP deficiency with pathogenesis of Schistosoma japonicum, a life-threatening parasite peculiar to this region. The eggs of S. japonicum showed slow embryonation when cultured in CETP-deficient human plasma. Restoration of CETP to the deficient plasma rescued it, while inhibition of CETP in normal plasma did not cause slow embryonation of the cultured eggs. The egg embryonation was also retarded in the liver but not in the intestine of wild-type mice in comparison to the CETP-transgenic mice. The granulomatous lesion around the parasite eggs in the liver was less in the wild-type than in the CETP-transgenic mice. Thus, CETP deficiency may act against Schistosomiasis japonica by retarding egg embryonation, a potential cause of liver granulomatosis. It does not seem directly due to the lack of CETP activity in plasma but to abnormal lipoprotein generated by chronic CETP deficiency.

[Usefulness of power Doppler ultrasound in a patient with renal cell carcinoma in the wall of a simple renal cyst].

We present a case of renal cell carcinoma in the wall of a simple renal cyst. A 54-year-old man visited our hospital with a complaint of right back pain. Ultrasound study revealed right hydronephrosis, a ureteral stone, and a 9 x 8 cm renal cyst, with a tumor, 2 cm in diameter, in the cyst wall. Power Doppler Ultrasound and enhanced computed tomography demonstrated hypervascularity of the tumor. Clinically, he was diagnosed as renal cell carcinoma and nephrectomy was performed. Pathological findings of the tumor showed clear cell carcinoma in the wall of a simple renal cyst. Twelve months after the nephrectomy, he was free from recurrence.

Caspase-independent cell death and mitochondrial disruptions observed in the Apaf1-deficient cells.

Apaf1 is a critical molecule in the mitochondria-dependent apoptotic pathway. Here we show that Apaf1-deficient embryonic fibroblasts died at a later phase of apoptotic induction, although these cells were resistant to various apoptotic stimulants at an early phase. Neither caspase 3 activation nor nuclear condensation was observed during this cell death of Apaf1-deficient cells. Electron microscopic examination revealed that death in response to apoptotic stimulation resembled necrosis in that nuclei were round and swollen with low electron density. Necrosis-like cell death was also observed in wild-type cells treated with z-VAD-fmk. Mitochondria were not only morphologically abnormal but functionally affected, since mitochondrial transmembrane potential (DeltaPsim) was lost even in cells with intact plasma membrane integrity. These mitochondrial alterations were also observed in the wild-type cells dying of apoptosis. Combined, these data suggest that cells without caspase activation, such as Apaf1-deficient cells or cells treated with caspase inhibitors, die of necrosis-like cell death with mitochondrial damage in response to "apoptotic stimulation."

A study of clinical features of cough variant asthma.

Patients with cough variant asthma (CVA) and classic asthma are frequently among subjects who present at clinics complaining of a chronic persistent cough. To reveal the features of CVA, we examined the differences in the clinical appearance between CVA and classic asthma. Ten CVA subjects and 11 classic asthmatics were enrolled in the study; they were recruited among patients who presented at the National Minamiokayama Hospital complaining of a chronic cough. The number of eosinophils in peripheral blood was 256 +/- 45.8/microl in CVA and 400 +/- 123/microl in classic asthma. Eosinophils represented 67% of the cells of sputum in CVA and 82% in classic asthma. Bronchial responsiveness to methacholine was Dmin 1.37 +/- 0.56 U in CVA and 0.71 +/- 0.46 U in classic asthma. There was no significant difference in these three parameters. There was only a significant difference in V25 between CVA and classic asthma, 80.0 +/- 6.9 and 52.2 +/- 10.0%, respectively. Eosinophil inflammation was almost the same in both CVA and classic asthma.

Ascorbic acid protects against peroxidative modification of low-density lipoprotein, maintaining its recognition by LDL receptors.

Peroxidatively modified low-density lipoprotein (LDL) may contribute to atherosclerotic processes; therefore, protecting LDL against peroxidation may thus reduce or retard the progression of atherosclerosis. We have evaluated the protective effects of ascorbic acid on copper-catalyzed LDL peroxidative modification. The protective effects of ascorbic acid on copper-catalyzed LDL peroxidative modification were examined by measurement of concentration of lipid hydroperoxides in LDL and by the provision of LDL cholesterol to lymphocytes via LDL receptor-mediated pathway. The measurement of concentration of lipid hydroperoxides in LDL showed that ascorbic acid inhibited peroxidative modification of LDL. Also, ascorbic acid preserved the ability of LDL to be recognized by LDL receptors in peripheral blood lymphocytes to the same extent as native LDL. These findings indicate that ascorbic acid may protect LDL against peroxidative modification, maintaining its ability to act as a ligand for LDL receptors in vivo.

Circadian rhythm and postural change in natriuresis in non-dipper type of essential hypertension.

Recently we found that, in non-dipper type of essential hypertensive patients who showed the lack of nocturnal fall in blood pressure, circadian rhythm of urinary sodium excretion rate was disturbed. In the present study we examined whether postural change in natriuresis is also disturbed in non-dippers. Sixteen inpatients with essential hypertension were maintained on a relatively high sodium diet containing 10 to 12 g of NaCl per day for 8 days. On the 7th day of the study period, 24-h ambulatory blood pressures were measured, and 5-7th days urinary samples were collected for both daytime and night-time. On the last day of the study period, patients stood for 2 h and then lay down for 2 h. Urinary volume and excretion rates of creatinine and sodium were measured every hour in both positions. Night-time urinary sodium excretion rate was significantly higher in non-dippers (n = 9) than that in dippers (n = 7). Night/day ratio of mean arterial pressure had a positive relationship with night/day ratio of urinary sodium excretion rate. In non-dippers, but not in dippers, the mean value of U(Na)V during upright position was significantly lower than that during supine position. There was a significantly negative relationship between upright/supine ratio of U(Na)V and night/day ratio of MAP or night/day ratio of U(Na)V. In patients with non-dipper type of essential hypertension, both natriuresis patterns, circadian rhythm and postural change, were disturbed.

Urothelial mucosal concentration of levofloxacin administered before transurethral resection: Is the mucosal concentration predictable?

BACKGROUND: Although it is an established surgical technique, transurethral resection (TUR) is associated with a certain incidence of postoperative bacteriuria. Assessment was made whether the urothelial mucosal concentration of an antibiotic administered before TUR was high enough to decrease the incidence of urinary tract infection (UTI). Also investigated were factors predicting the organ concentration. METHODS: Forty-nine patients (45 men and four women aged 51-79 years with a median age of 70 years) who underwent TUR between August 1996 and September 1997 were enrolled in the study. Each patient received 200 mg of levofloxacin (LVFX) about two hours before surgery. Blood and bladder urine were collected and urothelial mucosa was harvested at the time of TUR. Then the LVFX concentration in these samples was measured using high-performance liquid chromatography. The association between drug levels, or the ratio to the serum concentration, and factors likely to affect the vascular system that delivers the drug (age, bodyweight, blood pressure, pulse rate, total cholesterol and diabetes mellitus) were investigated. RESULTS: The mean serum drug level was 2.4 microg/mL, and it was 206.4 microg/mL in the urine and 5.7 microg/mL in the urothelial mucosa. The mean ratio of the mucosal to serum concentrations was 2.6. The urinary drug concentration showed no association with any of the factors assessed, while the serum concentration decreased with increasing bodyweight (P = 0.03). As the diastolic blood pressure increased, both the mucosal drug concentration and the mucosa/serum ratio decreased (P < 0.01). When the relationship between the serum and mucosal concentrations was investigated, no correlation was found. However, the mucosa/serum ratio (indicating the transfer of LVFX from the blood) was positively correlated with the mucosal concentration. CONCLUSION: Preoperative administration of LVFX was demonstrated to have potential value for the prophylaxis of UTI after TUR. Both the mucosal concentration and the mucosa/serum ratio were correlated with the diastolic blood pressure. As the diastolic blood pressure seems to be an indicator of the tissue concentration of LVFX, it may be possible to set the optimum dose based on the diastolic pressure.