Keiichi Shishido

The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat†‡

To develop a rat model of atherosclerosis‐induced chronic bladder ischemia and investigate the effect of chronic bladder ischemia on voiding behavior and bladder function.

Alpha1-Adrenoceptor Antagonists Improve Bladder Storage Function Through Reduction of Afferent Activity in Rats With Bladder Outlet Obstruction†‡

Using a rat BOO model, we determined whether α1‐adrenoceptor (AR) antagonists (silodosin, prazosin) improve the bladder storage function by reducing afferent input from the lower urinary tract.

Obstruction alters muscarinic receptor-coupled RhoA/Rho-kinase pathway in the urinary bladder of the rat†

The present study investigated the effects of the bladder outlet obstruction (BOO) on the muscarinic receptor (MR)‐coupled RhoA/Rho‐kinase (ROK) pathway in the detrusor smooth muscle of the rat.

Influence of Pelvic Floor Muscle Contraction on the Profile of Vaginal Closure Pressure in Continent and Stress Urinary Incontinent Women

PURPOSE We characterized the vaginal pressure profile as a representation of closure forces along the length and circumference of the vaginal wall. Vaginal pressure profile data were used to test the hypothesis that the strength of pelvic floor muscle contractions differs significantly between continent women and women with stress urinary incontinence. MATERIALS AND METHODS Vaginal pressure profile recordings were made in 23 continent subjects and in 10 patients with stress urinary incontinence. The recordings characterized closure forces along the entire length of the vagina and identified differences among the anterior, posterior, left and right sides of the vaginal wall. Using a novel, directionally sensitive vaginal probe we made vaginal pressure profile measurements with the women at rest and during pelvic floor muscle contraction while supine. RESULTS The nature of the vaginal pressure profile was characterized in terms of force distribution in the anterior and posterior vaginal walls, which was significantly greater than that on the left and right sides. The continent group had significant greater maximum pressure than the stress urinary incontinence group on the posterior side at rest (mean +/- SE 3.4 +/- 0.3 vs 2.01 +/- 0.36 N/cm(2)) and during pelvic floor muscle contraction (4.18 +/- 0.26 vs 2.25 +/- 0.41 N/cm(2)). The activity pressure difference between the posterior and anterior vaginal walls in the continent group was significantly increased when the pelvic floor muscles contracted vs that at rest (3.29 +/- 0.21 vs 2.45 +/- 0.26 N/cm(2)). However, the change observed in the stress urinary incontinence group was not significant (1.85 +/- 0.38 vs 1.35 +/- 0.27 N/cm(2)). CONCLUSIONS The results demonstrate that the voluntary pelvic floor muscles impose significant closure forces along the vaginal wall of continent women but not in women with stress urinary incontinence. The implication of these findings is that extrinsic urethral closure pressure is insufficiently augmented by pelvic floor muscle contraction in women with stress urinary incontinence.

Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α.

Interferon (IFN)‐α is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN‐α, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN‐induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN‐α on SOCS3 expression and cell proliferation was examined using IFN‐resistant 786‐O and IFN‐sensitive ACHN cell lines. The effects of SOCS3‐targeted siRNA on 786‐O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN‐α stimulation in 786‐O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth‐inhibitory effect of IFN‐α. Suppression of SOCS3 expression in 786‐O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN‐α. An in vivo study indicated that co‐administration of SOCS3‐targeted siRNA promoted IFN‐α‐induced cell death and growth suppression in 786‐O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3‐induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells. (Cancer Sci 2011; 102: 57–63)

Place of overactive bladder in male lower urinary tract symptoms

Lower urinary tract symptoms (LUTS) are highly prevalent in older men and women. Overactive bladder symptom syndrome (OAB) comprises the storage subset of LUTS and, in both sexes, is the most bothersome. The management of male LUTS has however, been disproportionately dominated in the past by an emphasis on prostatic pathology (bladder outlet obstruction (BOO) and prostatic enlargement). Pharmacotherapy that targets the prostate (e.g., α1-adrenoceptor antagonists) often fails to alleviate OAB symptoms, while many studies suggest that antimuscarinic therapy alone, or in combination with α1-adrenoceptor antagonists, can improve OAB symptoms in men with and without BOO. Recent studies suggest that arterial obstructive disease, such as atherosclerosis, may cause OAB in both men and women via ischemia, hypoxia and oxidative stress in the bladder. In this context, the use of phosphodiesterase inhibitors has been suggested to be a potential pharmacotherapy for men with LUTS. This article provides a review of the place of OAB in male LUTS and its treatment and provides an opportunity to draw data from a number of sources into one manuscript for critical review.

Effect of Long-Term Oxybutynin Administration on c-Fos Expression in Spinal Neurons: Inhibition of Antimuscarinics on Bladder Afferents in Conscious Rats

OBJECTIVES To investigate the effect of long-term administration of oxybutynin on afferent input from the bladder by evaluating c-Fos expression in the spinal cord. METHODS Using an osmotic pump, long-term administration of oxybutynin (4 weeks) was performed in the rat. The effects of oxybutynin (2 doses) on the urodynamic parameters were determined by continuous cystometry in conscious rats. After cystometry, c-Fos expression in the spinal cord was measured by immunohistochemistry. RESULTS The long-term administration of low-dose oxybutynin (0.36 mg/kg/d) significantly increased the micturition interval and bladder capacity, but it did not affect micturition pressure. However, administration of high-dose oxybutynin (3.6 mg/kg/d) significantly decreased the micturition pressure and increased the residual volume. In the rats that received low-dose oxybutynin, the number of c-Fos-positive neurons in the spinal cord was significantly lower than that in controls. CONCLUSIONS Administration of low-dose oxybutynin decreased the c-Fos expression induced by continuous infusion of saline into the bladder. This result suggests that the antimuscarinic drug oxybutynin at clinically recommended doses can exert an inhibitory effect on afferent input from the bladder during the storage phase without affecting detrusor contractions.

Spatial distribution of vaginal closure pressures of continent and stress urinary incontinent women.

Clinically the strength of the contraction of the female pelvic floor is qualitatively evaluated by vaginal tactile palpation. We therefore developed a probe to enable the quantitative evaluation of the closure pressures along the vagina. Four force sensors mounted on the four orthogonal directions of an intra-vaginal probe were used to measure the vaginal pressure profile (VPP) along the vaginal wall. Clinical experiments on 23 controls and 10 patients with stress urinary incontinence (SUI) were performed using the probe to test the hypothesis that the strength of pelvic floor muscle (PFM) contractions, imposed by voluntary contraction, is related to urinary continence. The results show that VPPs, characterized in terms of pressure distribution on the anterior and posterior vaginal walls, are significantly greater than those in the left and right vaginal walls. When the PFM contracted, the positions of the maximum posterior pressures in continent females and SUI patients were 0.63+/-0.15 cm and 1.19+/-0.2 cm proximal from their peak points of anterior pressure, which are 1.52+/-0.09 cm and 1.69+/-0.13 cm proximal from the introitus of vagina, respectively. The statistical analysis shows that the maximum posterior vaginal pressures of the controls were significantly greater than those of the SUI patients both at rest (continent: 3.4+/-0.3 N cm(-2), SUI: 2.01+/-0.36 N cm(-2), p<0.05) and during PFM contraction (continent: 4.18+/-0.26 N cm(-2), SUI: 2.25+/-0.41 N cm(-2), p<0.01). In addition, the difference between the posterior and anterior vaginal walls is significantly increased when the controls contract the PFM. By contrast, there are no significant differences in the SUI group. The results show that the VPP measured by the prototype probe can be used to quantitatively evaluate the strength of the PFM, which is a clinical index for the diagnosis or assessment of female SUI.

Strain-specific seroepidemiology and reinfection of cytomegalovirus.

Although there have been some reports describing the serostatus of cytomegalovirus, strain-specific antibody responses and their distribution remain unknown. In this study, ELISA using fusion proteins encompassing epitope of glycoprotein H from both AD169 and Towne strains was used to test 352 blood donors. Of these 352 donors, 207 were analyzed for strain-specific glycoprotein H antibodies. Of the 44 donors whose serum contained antibodies against both AD169 and Towne, 27 (60%) were aged 50 years or over (p = 0.0003). This may indicate serological evidence of reinfection with cytomegalovirus in the elder population. The nucleotide sequence analysis of cytomegalovirus glycoprotein H from the peripheral blood of the cytomegalovirus-positive renal transplant recipients showed that our strain-specific ELISA can reveal cytomegalovirus reinfection after transplantation.

The Association between Severity of Atherosclerosis and Lower Urinary Tract Function in Male Patients with Lower Urinary Tract Symptoms

Objectives: The present study was undertaken to investigate the association between the severity of atherosclerosis and lower urinary tract function in male patients with lower urinary tract symptoms.