The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: a multi-institutional retrospective study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. METHODS: The data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5-33.2). RESULTS: The median duration of nivolumab therapy was 7.1 months (IQR 2.9-24.4). The objective response rate was 25% and the 1- and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.1) and 3.3 (IQR 2.4-5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020). CONCLUSIONS: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor.

The angiotensin II type 1 receptor (AT1) is a 7-transmembrane domain GPCR that when activated by its ligand angiotensin II, generates signaling events promoting vascular dysfunction and the development of cardiovascular disease. Here, we show that the single-transmembrane oxidized LDL (oxLDL) receptor (LOX-1) resides in proximity to AT1 on cell-surface membranes and that binding of oxLDL to LOX-1 can allosterically activate AT1-dependent signaling events. oxLDL-induced signaling events in human vascular endothelial cells were abolished by knockdown of AT1 and inhibited by AT1 blockade (ARB). oxLDL increased cytosolic G protein by 350% in Chinese hamster ovary (CHO) cells with genetically induced expression of AT1 and LOX-1, whereas little increase was observed in CHO cells expressing only LOX-1. Immunoprecipitation and in situ proximity ligation assay (PLA) assays in CHO cells revealed the presence of cell-surface complexes involving LOX-1 and AT1. Chimeric analysis showed that oxLDL-induced AT1 signaling events are mediated via interactions between the intracellular domain of LOX-1 and AT1 that activate AT1. oxLDL-induced impairment of endothelium-dependent vascular relaxation of vascular ring from mouse thoracic aorta was abolished by ARB or genetic deletion of AT1. These findings reveal a novel pathway for AT1 activation and suggest a new mechanism whereby oxLDL may be promoting risk for cardiovascular disease.

Mid-term outcome of permanent prostate iodine-125 brachytherapy in Japanese patients.

OBJECTIVES: To analyze mid-term oncological outcomes of low-dose rate brachytherapy in Japanese patients. METHODS: Between 2003 and 2010, 604 consecutive patients with clinically localized prostate cancer were treated with low-dose rate brachytherapy at Jikei University Hospital in Tokyo, Japan. Median follow up was 48 months. Of these patients, 260 (43%) were treated with neoadjuvant therapy, 45 (7.5%) with adjuvant hormonal therapy and 75 (12.4%) with supplemental external beam radiation therapy. Biochemical recurrence was defined as the prostate-specific antigen nadir plus 2 ng/mL. RESULTS: Of the 604 patients, 219 (36.2%) were low risk, 361 (59.8%) were intermediate risk and 24 (4.0%) had high-risk disease. The median biologically effective dose was 174.4 Gy2. At 8 years, biochemical recurrence-free survival, cancer-specific survival, and overall survival were 82.2%, 100% and 95.6%, respectively. Biochemical recurrence-free survival at 8 years was 89.9%, 79.4% and 52.5%, for the low-, intermediate-, and high-risk groups, respectively. Biochemical recurrence-free survival for the high-risk group was significantly lower than the low- and intermediate-risk groups (P < 0.001). Biochemical recurrence-free survival did not differ significantly by biologically effective dose stratification. In multivariate analysis, younger age (P = 0.045), higher prostate-specific antigen (P = 0.004), higher Gleason score (P = 0.006) and higher clinical T stage (P = 0.008) were significant covariates associated with biochemical recurrence. The addition of hormonal therapy or external beam radiation therapy was associated with significantly better outcomes than low-dose rate brachytherapy monotherapy (P = 0.0021 and 0.010). Just four patients experienced G3 genitourinary or gastrointestinal toxicity. CONCLUSIONS: Low-dose rate brachytherapy results in excellent mid-term oncological outcomes and acceptable toxicity in Japanese patients. In our experience, biologically effective dose does not represent a significant predictor for biochemical recurrence.

[The prevalence of hypertension after adrenalectomy in patients with primary aldosteronism].

The cure rate of hypertension after surgery for primary aldosteronism (PA) was assessed in a single institution. In the present study, we studied the risk factors on the cure rate of hypertension after surgery in patients with PA. Thirty-five patients who underwent surgery for PA between January 2004 and December 2009, with a follow-up time of 1 year or longer were studied. The mean age at surgery was 50.7 years old. The male to female ratio was 24 : 11. Factors confounding the cure rate of hypertension after surgery were analyzed using the univariate and the multivariate analysis. Nineteen (54%) of the 35 patients were completely cured after surgery. In most cases, a complete cure was seen within 1 month after surgery. At 1 year after surgery, the dose of medication for hypertension could be decreased in 11 (13%) of the 16 non cured patients. Although hypertension in patients with PA may be curable by surgery, the cure rate of hypertension after surgery has been reported to be from 16 to 67%. In the present study, age, gender, preoperative serum creatinine, the period of hypertension, the number of medications for hypertension, and family history for hypertension were significant in the univariate analysis for the cure rate of hypertension (persistent hypertension) after surgery. Multivariate analysis showed that the age of 55 years old or older was a significant predictor for non-curable hypertension after surgery. Our result suggests that earlier surgery may contribute to a better outcome on the cure rate of postoperative hypertension in patients with PA.

The impact of hypertriglyceridemia on prostate cancer development in patients aged ≥60 years.

OBJECTIVE: • To investigate the relationship between serum triglyceride (TG) levels and the incidence and characteristics of prostate cancer detected on biopsy. PATIENTS AND METHODS: • We evaluated data from consecutive patients who underwent prostatic biopsy. Data analysed included age, total serum prostate-specific antigen (PSA) level, prostatic volume, body mass index (BMI), TG levels, and cholesterol-lowering medications. RESULTS: • We analysed data from 905 patients, including 528 (58.3%) with positive biopsy findings. • Using 150 mg/dL as the threshold point of TG levels, multivariate analysis yielded an adjusted odds ratio (OR) reflecting the association of higher TG levels with prostate cancer diagnosis of 1.66 (95% confidence interval (CI) 1.21-2.29, P = 0.002). • Pearson correlation coefficient analysis including age, PSA level, prostatic volume, BMI and TG, showed TG level significantly correlated with BMI (r = 0.185, P < 0.001). • In the analysis by age intervals (≤59, 60-69, and ≥70 years), the association between high TG levels and positive biopsy findings was enhanced in the age groups 60-69 and ≥70 years (OR 2.10, 95% CI 1.31-3.37, P = 0.002 and OR 1.91, 95% CI 1.03-3.53, P = 0.039, respectively), but not in the group aged ≤59 years. • In patients aged ≥60 years, high TG levels were statistically significantly associated with a Gleason score of ≥8. CONCLUSIONS: • High TG levels correlated well with a higher incidence of prostate cancer, especially in patients aged ≥60 years. • High TG levels were also associated with a Gleason score of ≥8 in this age group. • Our results suggest that elderly patients with high TG levels may be more vulnerable to the development of prostate cancer with an aggressive biology.

Expression of ERG oncoprotein is associated with a less aggressive tumor phenotype in Japanese prostate cancer patients.

To investigate and characterize ERG oncoprotein expression in Japanese patients with prostate cancer (PCa), we evaluated 92 index tumors from Japanese patients who had undergone radical prostatectomy for PCa, using an antibody-based detection method to determine ERG expression. Expression status was compared with clinicopathological findings including patient age, body mass index and preoperative prostate-specific antigen (PSA) levels, specimen Gleason score, pathological stage, positive surgical margin, size of index tumor, prostatic volume, zonal origin of index tumor and biochemical failure. Overall, ERG protein was expressed in 16.3% (15/92) of the index tumors, but not in benign glands. Younger patient age, lower Gleason score and negative surgical margins were found to be independently associated with its expression in the multivariate analysis (P= 0.015, 0.003 and 0.038, respectively). ERG expression was not associated with biochemical failure. Though not statistically significant, ERG expression was more frequently observed in peripheral zone than in transition zone cancers (28.2% vs 10%, respectively). In conclusion, ERG protein was less frequently expressed in this Japanese PCa cohort compared with Western reports. ERG expression was associated with a less aggressive tumor phenotype, and its biological significance needs to be further investigated.

Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome.

Although the pathogenesis of interstitial cystitis/bladder pain syndrome remains unknown, there is a significant correlation of interstitial cystitis/bladder pain syndrome with other chronic pain disorders, such as irritable bowel syndrome, endometriosis and fibromyalgia syndrome. In this review, we highlight evidence supporting neural cross-talk in the dorsal root ganglia, spinal cord and brain levels, which might play a role in the development of chronic pain disorders through central sensitization. In addition, we focus on transient receptor potential V1 and transient receptor potential A1 as the receptor targets for chronic pain conditions, because transient receptor potential V1 and transient receptor potential A1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons. Furthermore, peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of transient receptor potential V1 and transient receptor potential A1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously. The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk. Because oxidative stress is considered to induce activation of transient receptor potential A1, we also discuss exogenous and endogenous oxidative stress to elucidate its role in the pathogenesis of interstitial cystitis/bladder pain syndrome and other chronic pain conditions.

Staphylococcal nuclease domain-containing protein 1 as a potential tissue marker for prostate cancer.

Using high molecular-weight proteomic analysis, we previously showed that Staphylococcal nuclease domain-containing protein 1 (SND1) is highly expressed in recurrent androgen-insensitive prostate cancer tissues. SND1 is a component of the RNA-induced splicing complex that mediates RNA interference, leading to degradation of specific mRNAs. The objective of this study was to further characterize SND1 expression and to investigate its biological potential in prostate cancer. Radical prostatectomy specimens were obtained from 62 prostate cancer patients. SND1 immunohistochemical staining patterns were evaluated using an in-house polyclonal antibody. We confirmed SND1 mRNA expression in prostate cancer cells using an in situ hybridization technique. To determine the importance of SND1 mRNA, we knocked down SND1 in vitro with small interfering RNA and observed a significant decrease in cell growth. SND1 was expressed in 60 of 62 prostate cancers (97%), appearing in the cytoplasm as small, granular structures; it was also present at high levels in prostate cancer specimens, while in hyperplasia specimens and normal epithelium, it was weakly or negatively expressed. SND1 expression intensity increased with increasing grade and aggressiveness of the cancer. As SND1 mRNA was overexpressed in cancer cells, the growth of these cells was suppressed following SND1 knockdown in vitro, thus representing a promising prostate cancer biomarker and therapeutic target.

CT and MRI findings of a stromal tumour of uncertain malignant potential of the prostate.

Cystic neoplasms arising from the prostate are rare, and stromal tumours of uncertain malignant potential and the spectrum of cystic epithelial tumours of the prostate are the major differential diagnoses of a cystic prostatic neoplasm. We report a case of a stromal tumour of uncertain malignant potential, which showed a multilocular cystic mass with some solid components. The solid component of the tumour did not show substantial diffusion restriction and uptake of 18F-FDG-PET, and this could be the critical finding suggesting a stromal tumour of uncertain malignant potential rather than a malignant cystic epithelial tumour.

Macrophage inflammatory protein-1beta induced cell adhesion with increased intracellular reactive oxygen species.

UNLABELLED: To investigate the role of macrophage inflammatory protein-1 beta (MIP-1beta) in the development of atherosclerosis, we designed an in vitro study to elucidate the mechanisms of monocyte-endothelium adhesion via intracellular reactive oxygen species (ROS). Angiotensin II (AngII) was used as a positive control. Furthermore, we examined the efficacy of MIP-1beta as a predictor of stroke and cardiovascular events in hypertensive patients. MIP-1beta or AngII stimulation significantly increased ROS production and adhesion of THP-1 cells to inflamed human umbilical vein endothelial cells. Cell adhesion and ROS production were inhibited in stimulated THP-1 cells by: inhibition of ROS signaling with N-acetylcysteine, diphenyleneiodonium, or PEG-Catalase; inhibition of PI3Kgamma with siRNA or LY294002; and by Rac1 siRNA. The MIP-1 beta or AngII stimulation did not increase surface expression of integrins, very late antigen 4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1), but cell adhesion was reduced by using an antiVLA-4 or an antiLFA-1 antibody. Moreover, cell adhesion and ROS production stimulated with MIP-1beta or AngII were completely inhibited by fluvastatin. In our clinical study, patients with the highest quartile of MIP-1beta showed a higher risk of stroke and cardiovascular events by a Cox proportional-hazards model. In conclusion, MIP-1beta directly induced cell adhesion to endothelial cells through oxidative stress via PI3k-Rac1 cascades. Serum MIP-1beta level might be a useful predictor for cerebro-cardiovascular events in hypertensive patients. CONDENSED ABSTRACT: We designed an in vitro investigation to examine the role of MIP-1beta on the development of atherosclerosis, including cell adhesion involving CAMs and ROS production, compared with angiotensin II. Furthermore, we investigated the prognostic impact of MIP-1beta on stroke and cardiovascular events in hypertensive patients in a small cohort study.

Chemosensitization of gemcitabine-resistant human bladder cancer cell line both in vitro and in vivo using antisense oligonucleotide targeting the anti-apoptotic gene, clusterin.

OBJECTIVE: To characterize changes in clusterin (sCLU-2) expression in bladder cancer cells after continuous treatment with gemcitabine and to determine whether knockdown of sCLU-2 can re-introduce sensitivity of gemcitabine-resistant cells to treatment with gemcitabine. MATERIALS AND METHODS: A human bladder cancer cell line, UM-UC-3, was continuously exposed to increasing doses of gemcitabine in vitro, and a gemcitabine-resistant cell line UM-UC-3R was developed. The role of sCLU-2 in chemoresistant phenotype acquired in both in vitro and in vivo was then analysed using antisense oligonucleotide targeting the sCLU-2 gene (OGX-011). RESULTS: Treatment of parental UM-UC-3 cells (UM-UC-3P) with gemcitabine induced transient up-regulation of sCLU-2 protein. There was a sustained increase in sCLU-2 expression levels in UM-UC-3R compared with UM-UC-3P cells (6.4-fold). Treatment of UM-UC-3R cells with OGX-011 resulted in a dose-dependent and sequence- specific inhibition in sCLU-2 expression. Furthermore, OGX-011 chemo-sensitized UM-UC-3R cells to gemcitabine in vitro with a reduction in the concentration that reduces the effect by 50% (IC50) from 100 nm to 10 nm. Tumour volume and the incidence of metastasis in nude mice injected with UM-UC-3R cells was significantly greater than those of nude mice injected with UM-UC-3P cells; however, systemic administration of OGX-011 plus a low dose of gemcitabine significantly suppressed tumour volume and the incidence of metastasis in both groups. CONCLUSION: These findings suggest that sCLU-2 plays a significant role in the acquisition of chemoresistant phenotype in bladder cancer cells and the knockdown of sCLU-2 using OGX-011 combined with a chemotherapeutic agent could be an attractive approach for advanced bladder cancer through the enhancement of chemosensitivity.

GLI2 knockdown using an antisense oligonucleotide induces apoptosis and chemosensitizes cells to paclitaxel in androgen-independent prostate cancer.

PURPOSE: GLI transcription factors mediate hedgehog signaling and have been implicated in several human malignancies, including prostate cancer. The objectives of this study were to characterize GLI2 expression levels in human prostate cancer cell lines and tissues to test the effect of antisense oligonucleotide (ASO) targeting GLI2 on androgen-independent (AI) prostate cancer cell lines. EXPERIMENTAL DESIGN: A tissue microarray was used to characterize differences in GLI2 expression in benign prostate hyperplasia, prostate cancer treated by neoadjuvant hormonal therapy and AI prostate cancer. The effects of GLI2 ASO on PC-3 cell growth and paclitaxel chemosensitivity were assessed in vitro and in vivo. Oligonucleotide spotted microarray analysis was used to determine alteration in GLI2 coregulated genes after ASO treatment. RESULTS: The expression of GLI2 was significantly higher in prostate cancer than in benign prostate hyperplasia, decreased after androgen ablation in a time-dependent fashion, but became highly expressed again in AI prostate cancer. GLI2 ASO treatment of PC-3 cells reduced GLI2 mRNA and protein levels in a dose-dependent manner. GLI2 knockdown increased PC-3 cell apoptotic rates and significantly decreased cell growth and modulated levels of apoptosis-related genes, such as Bcl2, Bcl-xL, and clusterin. GLI2 knockdown also changed levels of several cell cycle regulators, such as cyclin D1, p27, and PKC-eta. Systematic administration of GLI2 ASO in athymic mice significantly delayed PC-3 tumor progression and enhanced paclitaxel chemosensitivity. CONCLUSIONS: These findings suggest that increased levels of GLI2 correlates with AI progression and that GLI2 may be a therapeutic target in castrate-resistant prostate cancer.

Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity.

OBJECTIVES: Microtubular inhibitors, including docetaxel, are active cytotoxics in many cancers, including prostate cancer (CaP). The Eg5 gene, a member of the kinesin-5 family, plays critical roles in proper mitotic spindle function, and is a potential microtubule-related target for proliferating cancer cells. To investigate the functional activities of Eg5 in CaP, we used an antisense oligonucleotide (ASO) targeting Eg5 to assess the potency and anti-cancer activity of Eg5 ASO treatment for androgen-independent CaP cells in vitro and in vivo. RESULTS: PC3 cells express higher Eg5 protein and mRNA levels compared to LNCaP cells. In both cell lines, Eg5 ASO treatment reduced mRNA and protein levels in a dose-dependent manner and a complete reduction of Eg5 protein levels was observed at 100 nM. Dose-dependent inhibition in cell growth, potent G2/M phase arrest, and increases in apoptotic sub-G1 fraction were also observed using Eg5 ASO. Surprisingly, low dose Eg5 ASO significantly antagonized cytotoxic effects of paclitaxel. In vivo, Eg5 ASO monotherapy significantly reduced both LNCaP and PC-3 tumor growth but combination treatment with paclitaxel did not yield additive benefits. CONCLUSIONS: These findings suggest that while Eg5 is a potential target to delay androgen-independent CaP growth, combination treatment with paclitaxel may not be desirable.

The maximum tumour length in biopsy cores as a predictor of outcome after radical prostatectomy.

OBJECTIVES: To evaluate maximum tumour length (MTL) in biopsy cores as a predictor of prostate-specific antigen (PSA)-failure, systemic failure, and death from prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS: We assessed 209 men with clinically localized prostate cancer treated with RP; preoperative variables were correlated with unfavourable pathological characteristics in the RP specimens and with outcome after surgery, using univariate and multivariate analysis. RESULTS: The median (range) MTL was 4 (0.2-19) mm and correlated with adverse pathological findings, including specimen Gleason score (P = 0.003), pT3 (P < 0.001), seminal vesicle invasion (P < 0.001) and lymph node involvement (P = 0.019) in multivariate analysis. Preoperative PSA (P < 0.001), biopsy Gleason score (P = 0.002), and MTL (P = 0.045) were independent predictors of PSA failure, whereas only MTL remained a predictor of systemic-failure (P < 0.001) and death from prostate cancer (P = 0.004). The median (range) follow-up after surgery was 90 (17-152) months, during which 83 patients had PSA failure, 20 developed systemic failure and 15 died from prostate cancer. CONCLUSIONS: The MTL correlates well with adverse pathological findings and appears to be an independent predictor of outcome after RP. Patients with a greater MTL might have cancer with an aggressive phenotype and therefore be candidates for more aggressive therapies.

SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1.

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

Renin-angiotensin inhibition reverses advanced cardiac remodeling in aging spontaneously hypertensive rats.

BACKGROUND: Many experiments using young hypertensive animal models support the evidence that angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 blocker attenuates the progression of cardiac hypertrophy. However, it is still unclear whether inhibiting the renin-angiotensin system can reverse age-related cardiac hypertrophy. To clarify the role of renin-angiotensin system inhibition in naturally advanced myocardial hypertrophy we treated spontaneously hypertensive, aging rats with an angiotensin-converting enzyme inhibitor or an angiotensin receptor type 1 blocker. METHODS: We used osmotic pumps to deliver the blood-pressure reducers temocaprilat, olmesartan, hydralazine, or saline for 4 weeks. RESULTS: Heart and body weights were significantly reduced in animals treated with temocaprilat or olmesartan compared with animals treated with hydralazine or saline. Histologic myocyte size and cardiac fibrosis were significantly attenuated by temocaprilat or olmesartan. Real-time polymerase chain reaction (PCR) revealed that temocaprilat or olmesartan suppressed expression of cardiac transforming growth factor-beta1 and fibroblast growth factor-2 mRNA, a marker of cardiac fibrosis. Cardiac and systemic oxidative stress assessed by 8-isoprostane levels was significantly reduced in animals treated with temocaprilat or olmesartan compared with hydralazine-treated or saline-treated rats. Renin-angiotensin system inhibition reduced cardiac expression of NAD(P)H oxidative components p22phox, p47phox, and gp91phox. CONCLUSIONS: Renin-angiotensin system inhibition can reverse age-related, advanced cardiac hypertrophy. The mechanism of reversal is partly due to suppression of cardiac oxidative stress.

Renal-protective effect of T-and L-type calcium channel blockers in hypertensive patients: an Amlodipine-to-Benidipine Changeover (ABC) study.

Both strict blood pressure control and efferent artery dilatation are critical in reducing proteinuria, which in turn helps to regulate blood pressure. Benidipine, an L- and T-type calcium channel blocker, has the potential for increased effectiveness compared with L-type-dominant calcium channel blockers such as amlodipine. Therefore, we evaluated blood pressure and proteinuria after changeover from amlodipine to benidipine in poorly controlled hypertensive patients. Fifty-eight hypertensive outpatients undergoing amlodipine treatment and unable to achieve optimal blood pressure as determined by Japanese Society of Hypertension Guidelines for the Management of Hypertention (JSH 2004) were changed over to benidipine treatment. We measured blood pressure and pulse rate and assessed urinary protein excretion before and after changeover. Systolic and diastolic blood pressure dropped from 151/90 mmHg to 140/81 mmHg (p<0.0001). Mean blood pressure (p<0.0001) and pulse pressure (p=0.0069) were also reduced, but pulse rate increased from 75 bpm to 78 bpm (p=0.0047). Urinary protein excretion adjusted for urinary creatinine was reduced from 0.35 +/- 0.82 to 0.22 +/- 0.55 g/g creatinine (p=0.0119). The urinary protein reduction was observed only in patients with renin-angiotensin inhibition (p=0.0216). By switching from amlodipine to benidipine treatment, more than 80% of patients reduced their blood pressure, and more than 40% achieved optimal blood pressure. Higher urinary protein excretion (p<0.0001), lower glomerular filtration rate (p=0.0011) and presence of diabetes (p=0.0284) were correlated with reduction of urinary proteins during changeover. Taken together, our results suggest that benidipine may have greater efficacy than amlodipine in reducing blood pressure and proteinuria.

Renal protective effect in hypertensive patients: the high doses of angiotensin II receptor blocker (HARB) study.

Angiotensin receptor blockers (ARBs) are the recommended first-line antihypertensive treatment for managing chronic kidney disease, and strict blood pressure (BP) regulation is crucial for the reduction of proteinuria. Valsartan and candesartan are commonly used ARBs in Japan, with maximum permissible doses of 160 mg/day and 12 mg/day, respectively. We evaluated BP and proteinuria after changeover from the maximum dose of candesartan to the maximum dose of valsartan, in 55 poorly controlled hypertensive patients undergoing candesartan treatment who were unable to achieve optimal BP according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). We measured BP and pulse rate and assessed urinary protein excretion (UPE) before and after changeover. Changeover was associated with decreases in systolic BP and diastolic BP from 158/89 mmHg to 150/86 mmHg (p<0.01). Changeover was also associated with a reduction in UPE adjusted to urinary creatinine from 0.35+/-0.19 g/g creatinine to 0.19+/-0.37 g/g creatinine (p=0.0271) in patients who had high urinary protein levels prior to changeover without significant decreases in BP (p=0.0184). According to multiple regression analysis, higher UPE (p<0.0001) and a lower glomerular filtration rate (GFR) (p=0.0011) prior to changeover were independently correlated with reduction in UPE. Our results suggest that the maximum dose of valsartan is more effective than the maximum dose of candesartan for reducing BP and proteinuria.

Clinical usefulness and limitations of brachial-ankle pulse wave velocity in the evaluation of cardiovascular complications in hypertensive patients.

The goal of this study was to clarify the clinical usefulness and limitations of brachial-ankle pulse wave velocity (PWV) to evaluate hypertensive complications, in comparison with carotid-femoral PWV. Patients with essential hypertension (n=296, male/female=161/135; age=61.1+/-0.7 years) were enrolled. We measured brachial-ankle PWV, femoral-ankle PWV and carotid-femoral PWV simultaneously, and evaluated target organ damage and associated clinical conditions (cerebrovascular and cardiovascular disease) using the World Health Organization classification modified in 1999. Carotid-femoral PWV (p<0.0001; r=0.521) and brachial-ankle PWV (p<0.0001; r=0.478) but not femoral-ankle PWV were significantly correlated with age. Carotid-femoral PWV was significantly higher in patients with associated clinical conditions compared with that in patients with target organ damage (p<0.05) and those with no complications (p<0.0001). Brachial-ankle PWV was significantly higher in patients with associated clinical conditions (p<0.05) and target organ damage (p<0.05) compared to those with no complications, but there was no significant difference in brachial-ankle PWV between these two groups. Moreover, femoral-ankle PWV was significantly lower in patients with associated clinical conditions compared with that in patients with target organ damage (p<0.05). These data suggest that brachial-ankle PWV could underestimate arterial stiffness in hypertensive patients with a history of cardiovascular events.

Evaluation of morning blood pressure elevation and autonomic nervous activity in hypertensive patients using wavelet transform of heart rate variability.

To evaluate morning autonomic nervous activity and blood pressure profiles in hypertensive patients by analyzing heart rate variability and ambulatory blood pressure. Data from 82 patients with untreated essential hypertension were analyzed. We evaluated the 24-h profile of blood pressure and that of indices of autonomic nervous activity, i.e., the high frequency component (HF) and low frequency component/HF (LF/HF), which were obtained by wavelet transform of heart rate variability. Patients were classified by dipping status (nondippers, n=28; dippers, n=32; extreme-dippers, n=8; and risers, n=14) and morning blood pressure profile (large, n=9; small, n=60; and inverted, n=13). Nocturnal systolic blood pressure in extreme-dippers was significantly lower than that in the other groups; that in the risers was significantly higher (p<0.05). There were no significant group differences in daytime systolic blood pressure. Daytime and 24-h HF levels were significantly higher in the dipper vs. the riser group (p<0.05). Morning blood pressure elevation negatively correlated to preawake (p<0.01) and nocturnal blood pressure (p<0.05), but not to daytime and post-awake blood pressure. The preawake/postawake ratio of systolic blood pressure positively correlated to that of LF/HF (p<0.01) and negatively correlated to preawake HF levels (p<0.05). Multivariate regression analysis revealed that preawake HF levels (p=0.037) and preawake/postawake ratio of LF/HF (p=0.033) were independently correlated with morning blood pressure elevation ratio. Our results suggest that activation of HF before waking and LF/HF during waking might play an important role in the development of morning blood pressure elevation.