Kanya Kaga

Neuromodulation for the Treatment of Lower Urinary Tract Symptoms

Neuromodulation therapy incorporates electrical stimulation to target specific nerves that control lower urinary tract symptoms (LUTS). The objectives of this article are to review the mechanism of action, the type of neuromodulation, and the efficacy of neuromodulation mainly according to the results of randomized controlled trials. Neuromodulation includes pelvic floor electrical stimulation (ES) using vaginal, anal and surface electrodes, interferential therapy (IF), magnetic stimulation (MS), percutaneous tibial nerve stimulation, and sacral nerve stimulation (SNS). The former four stimulations are used for external periodic (short‐term) stimulation, and SNS are used for internal, chronic (long‐term) stimulation. All of these therapies have been reported to be effective for overactive bladder or urgency urinary incontinence. Pelvic floor ES, IF, and MS have also been reported to be effective for stress urinary incontinence. The mechanism of neuromodulation for overactive bladder has been reported to be the reflex inhibition of detrusor contraction by the activation of afferent fibers by three actions, i.e., the activation of hypogastric nerve, the direct inhibition of the pelvic nerve within the sacral cord and the supraspinal inhibition of the detrusor reflex. The mechanism of neuromodulation for stress incontinence is contraction of the pelvic floor muscles through an effect on the muscle fibers as well as through the stimulation of pudendal nerves. Overall, cure and improvement rates of these therapies for urinary incontinence are 30–50, and 60–90% respectively. MS has been considered to be a technique for stimulating nervous system noninvasively. SNS is indicated for patients with refractory overactive bladder and urinary retention.

The role of muscarinic receptor subtypes on carbachol-induced contraction of normal human detrusor and overactive detrusor associated with benign prostatic hyperplasia

The aim of this study was to compare the effect of antimuscarinic antagonists on carbachol-induced contraction of normal human bladder and detrusor overactivity associated with benign prostatic hyperplasia (DO/BPH). Samples of human bladder muscle were obtained from patients undergoing total cystectomy for bladder cancer (normal bladder), and those undergoing retropubic prostatectomy for BPH. All of the patients with DO/BPH had detrusor overactivity according to urodynamic studies. Detrusor muscle strips were mounted in 10-ml organ baths containing Krebs solution, and concentration-response curves for carbachol were obtained in the presence of antimuscarinic antagonists (4-DAMP, methoctramine, pirenzepine, tolterodine, solifenacin, trospium, propiverine, oxybutynin, and imidafenacin) or vehicle. All antagonists competitively antagonized concentration-response curves to carbachol with high affinities in normal bladder. The rank order of mean pA2 values was as follows: trospium (10.1) > 4-DAMP (9.87), imidafenacin (9.3) > solifenacin (8.8) > tolterodine (8.6) > oxybutynin (8.3) > propiverine (7.7) > pirenzepine (7.4) > methoctramine (6.6). The effects of these antimuscarinic antagonists did not change when tested with DO/BPH bladder, suggesting that each antimuscarinic antagonist has a similar effect in this condition. Schild plots showed a slope corresponding to unity, except for propiverine with DO/BPH detrusor. In conclusion, M3-receptors mainly mediate contractions in human bladder strips with normal state and DO/BPH.

Six-year follow up of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: What are the factors for continuation or withdrawal?

To investigate the factors for continuation or withdrawal as an extension of a prospective study of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia for more than 6 years.

Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets

Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.

Therapeutic effect of propiverine hydrochloride on mixed-type urinary incontinence in women: The Female Urgency and Stress Urinary Incontinence Study of Propiverine Hydrochloride trial

To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed‐type urinary incontinence.

Effects of magnetic stimulation on urodynamic stress incontinence refractory to pelvic floor muscle training in a randomized sham-controlled study

The aim of the present study was to evaluate the effect of magnetic stimulation on urodynamic stress incontinence refractory to pelvic floor muscle training in a randomized sham‐controlled study.

Autologous and heterotopic transplantation of adipose stromal vascular fraction ameliorates stress urinary incontinence in rats with simulated childbirth trauma

Introduction Autologous transplantation of adipose stromal vascular fraction (SVF) is a cost-effective and technically accessible option for cell therapy. Clinical study of SVF transplantation for male stress urinary incontinence (SUI) is underway, but the effectiveness remains unknown for female SUI, majority of which is caused by childbirth trauma. Methods Vaginal Distension (VD) rats were generated as in vivo model for female SUI. To quantitate the severity of SUI, leak point pressure (LPP) was measured by placing a bladder catheter. There was a characteristic waveform of LPP with two-peaks, and we counted the second peak as an LPP value. Adipose SVF was separated from inguinal fat and delivered into external urethral sphincter (EUS) through transperineal injection. LPP was measured 7 or 14 days after SVF transplantation. Tissue damage and collagen synthesis around the EUS were visualized by Massons trichrome and eosin staining. Antibody against α-smooth muscle actin (α-SMA) was used to stain smooth muscle or activated stromal cells. Donor SVF cells were distinguished from recipient EUS tissue by tracking with GFP transgene. Results VD procedure decreased the frequency at which the normal LPP waveform appeared and lowered the LPP value. SVF injection normalized the waveform as well as the level of LPP. VD disrupted histological structure of EUS and SVF failed to differentiate into striatal muscles. Instead, SVF increased α-SMA positive cells and collagen synthesis but the phenomena depended on VD stimulus. GFP tracking indicated that the transplanted SVF cells persisted for four weeks and synthesized α-SMA protein simultaneously. Conclusions Autologous transplantation of adipose SVF displayed bulking effects through collagen synthesis. However, such heterotopic activation was dependent on tissue damage.

Extravasation of Urine Associated with Bilateral Complete Ureteral Duplication, Vesicoureteral Reflux and Benign Prostatic Hyperplasia

We report a rare case of extravasation of urine, which may be associated with bilateral complete ureteral duplication, vesicoureteral reflux (VUR), and benign prostatic hyperplasia (BPH). A 71-year-old male presented with a complaint of right abdominal pain. An extravasation of urine was noted, and was improved by indwelling urethral catheterization. Transurethral resection of the prostate and the endoscopic subureteral injection of dextanomer/hyaluronic acid were performed for the treatment of BPH and VUR, respectively. The post-surgery recovery was successful.

Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms

A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patients PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally. However, it increased up to 517.0 ng/ml thereafter. Consequently, a year after CAB, abiraterone acetate (AA) was initiated at a standard dose of 1,000 mg daily in combination with 10 mg of prednisolone. PSA rapidly decreased to the nadir of 20.1 ng/ml thereafter. The PSA level remained stable until 2 years after AA administration. However, he decided to reduce the dose of AA to half of the standard dose (500 mg daily). Contrary to our expectations, the serum PSA level promptly decreased to a nadir of 8.1 ng/ml. Thereafter, the PSA level remained stable until 3 years and 9 months after AA administration. Subsequently, the patient stopped taking AA and prednisolone. However, to our surprise, the patients serum PSA level decreased further to <1.0 ng/ml after AA discontinuation. His PSA remained <1.0 ng/ml without clinical or radiological progression for 1 year after AA withdrawal. Recently, it was reported that cessation of AA is associated with AA withdrawal syndrome in metastatic castration-resistant prostate cancer, defined as a PSA decrease after AA discontinuation, mimicking anti-androgen withdrawal syndrome. In the present study, explanations of the mechanisms underlying this phenomenon were explored, including mutant AR activation by alternative ligands.