Bacteraemia and obstructive pyelonephritis caused by Bifidobacterium breve in an elderly woman: a case report and literature review.

Bifidobacterium spp. are non-spore-forming Gram-positive anaerobes that are indigenous to the human gastrointestinal tract and vagina. They are believed to be non-pathogenic organisms for humans and thus are widely used as probiotics. An 83-year-old woman taking cephalexin for 4 days was diagnosed with obstructive pyelonephritis. Y-branched Gram-positive rods were found in both anaerobic and aerobic blood culture bottles, and in an anaerobic urine culture. Bifidobacterium breve was finally identified. Ceftriaxone and metronidazole were administered to the patient, and she was discharged after intermittent catheterization for dysuria. Urinary tract infection caused by Bifidobacterium spp. is believed to be rare, but it can develop in patients with underlying urological conditions. Recognition of the characteristic morphology and conducting anaerobic urine culture may help in identifying more cases of Bifidobacterium urinary tract infections.

Impact of Different Treatments for Disseminated Intravascular Coagulation on Patients with or without Biliary Drainage for Severe Biliary Tract Infection.

Objective: Sepsis caused by severe acute cholangitis requires biliary drainage to decrease the intra-biliary pressure. Furthermore, several studies showed that anticoagulant treatment can improve the outcomes of patients with sepsis-associated disseminated intravascular coagulation (DIC). There were reports examining the efficacy of anti-DIC drugs in patients undergoing biliary drainage with sepsis-associated DIC, and no reports compared the efficacy of DIC treatments when no drainage is performed. In this study, the influence of antithrombin (AT) replacement therapy and recombinant thrombomodulin (rTM) preparations on the overall survival (OS) of patients with and without biliary drainage was analyzed. Patients and Methods: This retrospective cohort study in a single institution involved patients with sepsis-associated DIC caused by severe biliary tract infection. In total, 71 patients treated by either AT replacement therapy or rTM preparation were assessed for inclusion. The two groups were patients with biliary drainage (n = 45) and without drainage (n = 26). To assess the clinical efficacy of anti-DIC drugs in each group, the 60-day OS was determined through estimated survival analysis. Results: Focusing on the effects of different therapeutic agents for DIC, in the group of patients with biliary drainage, OS showed no difference between patients treated by rTM and AT. However, in patients without biliary drainage, the survival curves of patients treated with AT replacement were lower than those of patients with rTM preparation. Conclusion: This study revealed that the OS of patients without biliary drainage differed depending on the DIC therapeutic agent for sepsis-associated DIC caused by acute cholangitis. We would recommend the use of rTM preparation over AT replacement therapy for patients who cannot undergo biliary drainage.

Pyogenic spondylitis following endoscopic submucosal dissection for early gastric cancer.

A man in his 80s who had a history of diabetes mellitus and aortic valve replacement was referred to our hospital for treatment of early gastric cancer and underwent endoscopic submucosal dissection (ESD). Three days after ESD, the patient presented with low back pain and fever (38.7°). We initially considered adverse events associated with gastric ESD such as delayed perforation. Moreover, thromboembolism and infectious endocarditis were suspected because of his medical history. However, there were no remarkable findings suggestive of these diseases. Finally, based on the results of blood cultures and MRI, the diagnosis of pyogenic spondylitis (PS) was made. We administered antibiotics for 12 weeks, and the patient improved without neurological impairments. This case indicates that bacteraemia and subsequent PS can occur following gastric ESD. Physicians should not overlook the patient's physical signs related to various adverse events after ESD.

Direct clipping using underwater inversion method for colonic diverticular bleeding.

Video 1Endoscopic direct clipping using an underwater inversion method for diverticular bleeding in the descending colon.

Sustained Eosinophilic Cholangitis Due to a Mite Allergy Mimicking Sclerosing Cholangitis.

Eosinophilic cholangiopathy (EC) presents with thickening and stenosis of the bile duct wall that is histologically characterized by eosinophil infiltration. The diagnosis is often difficult. We herein report a patient who had been followed up with a diagnosis of primary sclerosing cholangitis but had a final diagnosis of EC based on eosinophilia, histological findings of bile duct and liver biopsy specimens, and a review of a previous surgical specimen of the gallbladder. Antigen tests, isolation from her house, and accidental re-exposure to the antigen revealed that the causative antigen was the mite Dermatophagoides pteronyssinus.

A small pilot study to evaluate the accuracy and feasibility of a novel automated voiding diary device for recording urine output measurements.

AIMS: Recording a voiding diary can be bothersome for patients and is sometimes inaccurate and unhygienic. This study aimed to develop and assess the accuracy and convenience of a novel device that automatically records the voiding diary by measuring pre- and post-void body weight. METHODS: We used this novel device for seven healthy volunteers and ten hospitalized patients. The examinees got on the device before and after voiding and the device recorded the voiding diary automatically. The examinees also manually recorded a voiding diary by collecting their urine in a cup and measuring its volume and weight. We examined the correlation between the traditional and the automated voiding diary to confirm the accuracy of voiding measurements using this device. Additionally, we investigated which measurement method was preferred by the participants. RESULTS: In the healthy volunteers group, there was a strong correlation between the voided urine weight recorded by the device and voided urine weight measured manually by the examinee (R2 = 0.9935). In the patients group, there was a strong (R2 = 0.9117) but lower correlation than that of the volunteers group, with an error of ±25 g 62% of the time, and ±50 g 82% of the time, respectively. All of the healthy volunteers and seven of the ten patients preferred using the automated voiding diary. CONCLUSIONS: This novel device recorded a reasonably accurate voiding diary for everyday clinical practice.

Therapeutic effect of adipose-derived regenerative cells on bladder function in rats with underactive bladder.

We examined the effect of adipose-derived regenerative cells (ADRC) on bladder functions in a rat model of detrusor underactivity (DU) induced by bladder over-distention. Adult female Sprague Dawley rats were divided into 3 groups: sham group (control); over-distention group; and over-distention with ADRC treatment group. Bladder was over-distended with saline (2.7mL) on day 1, 8, 15 and 22 of the study. ADRCs, which were harvested from male F344 rats, expanded via culture, were injected into the bladder wall at day 15. Cystometry and in vitro organ bath functional studies were performed on day 28. Moreover, histological assessment of the bladder was performed. In cystometry, significant prolongation of the inter-contraction interval (ICI) and decrease of voiding efficiency (VE) were observed in the over-distention group, compared to that in the control group. Significant improvement in ICI and VE was seen in the ADRC treatment group in comparison with the over-distention group. The over-distention group showed significantly weaker bladder contractile responses to carbachol and electrical field stimulation than the control group, while bladder contractile responses were significantly stronger in the ADRC treatment group than that in the over-distention group. The over-distention group showed substantial fibrosis of the bladder compared to the control group, whereas bladder fibrosis was alleviated in the ADRC treatment group. In conclusion, the injection of ADRC into bladder wall improved bladder dysfunction and histological changes induced by bladder over-distention. ADRCs-based regenerative therapy could be novel treatment for DU.

Clinical characteristics and useful signs to differentiate detrusor underactivity from bladder outlet obstruction in men with non-neurogenic lower urinary tract symptoms.

OBJECTIVE: To investigate the clinical characteristics and useful signs to differentiate detrusor underactivity from bladder outlet obstruction in men with non-neurogenic lower urinary tract symptoms. METHODS: A total of 638 treatment-naive men with non-neurogenic lower urinary tract symptoms who underwent subjective and objective evaluations were reviewed retrospectively. We divided the patients into detrusor underactivity and bladder outlet obstruction groups based on urodynamic findings, and compared parameters obtained from questionnaires and non-invasive tests. Detrusor underactivity was defined as bladder contractility index ≤100 and bladder outlet obstruction index ≤40, whereas bladder outlet obstruction was defined as bladder contractility index >100 and bladder outlet obstruction index >40. RESULTS: Of 638 patients, 145 (22.7%) had detrusor underactivity and 273 (42.8%) had bladder outlet obstruction. Total international prostate symptom score and international prostate symptom score-voiding subscore were significantly higher in the detrusor underactivity group. There were significant differences in prostate volume, intravesical prostatic protrusion, and all uroflowmetry parameters between the two groups. In multivariate logistic regression analysis, lower intravesical prostatic protrusion (cut-off value 8.2 mm), lower bladder voiding efficiency (cut-off value 70%), and the presence of sawtooth and interrupted waveform on uroflowmetry were significant predictive factors for detrusor underactivity. In particular, the incidence of sawtooth and interrupted waveform was significantly higher in the detrusor underactivity group (80%) than in the bladder outlet obstruction group (12.8%), which showed both high sensitivity (80%) and specificity (87.2%) in differentiating detrusor underactivity from bladder outlet obstruction. CONCLUSIONS: Sawtooth and interrupted waveform on uroflowmetry can be a useful predictive factor for detrusor underactivity. In addition, lower intravesical prostatic protrusion and bladder voiding efficiency can be of supplementary use.

Pre-treatment serum testosterone level can be a useful factor to predict the improvement in bladder outlet obstruction by tadalafil for male patients with lower urinary tract symptoms induced by benign prostatic obstruction.

INTRODUCTION: To investigate possible pre-treatment factors related to the therapeutic effect of tadalafil on bladder outlet obstruction (BOO). MATERIALS AND METHODS: Eighty untreated outpatients with lower urinary tract symptoms (LUTS) due to BOO received 5 mg tadalafil daily for 12 months. Subjective symptoms and objective findings were evaluated before and 12 months after treatment. At 12 months, the patients were divided into two groups according to an improvement grade in BOO index (BOOI). Patient characteristics including age, serum total testosterone level (TT), PSA, and prostate volume, and subjective and objective parameters on LUTS were set as candidates of pre-treatment factors, and the parameters that influenced the improvement of BOO were statistically analysed. RESULTS: A total of 69 patients with mean age of 69.8 years and mean prostate volume of 48.8 mL were included. Subjective symptoms and BOOI were significantly ameliorated after 12 months. In terms of an improvement of BOOI, 30 patients (43.5%) showed insignificant improvement in BOO, whereas 39 patients (56.5%) exhibited excellent improvement. Comparison of pre-treatment factors between the groups showed that TT was the only independent predictor related to the improvement in BOO. The improvement of BOO was significantly better in patients with higher TT. CONCLUSIONS: Pre-treatment TT was considered to be a useful predictor of therapeutic effects of tadalafil for BOO.

What Are Factors Contributing to Improvement of Overactive Bladder Symptoms after Alpha-1 Blocker Treatment in Patients with Both Storage and Voiding Symptoms?

INTRODUCTION: To determine the pre-treatment factors related to the improvement of overactive bladder (OAB) symptom after alpha-1 blocker monotherapy in patients with benign prostatic hyperplasia complicated by OAB (BPH/OAB). METHODS: Post-hoc analysis of a prospective study in patients with BPH/OAB, randomized to receive silodosin 8 mg (n = 157) or naftopidil 75 mg (n = 157) treatment for 12 weeks, was performed. At 12 weeks post-administration, patients were divided into 2 groups (good responder [GR] group and poor responder [PR] group), according to the improvement in the OAB symptom score (OABSS). We compared the pre-administration parameters between both groups and evaluated the factors related to OAB improvement. RESULTS: Of 314 patients, 159 patients (50.6%) were classified into the GR and 155 (49.4%) into the PR. International Prostate Symptom score, total OABSS, OABSS urgency-score, OABSS urgency urinary incontinence (UUI)-score, post-void residual urine volume (PVR), and selection rate of naftopidil were significantly higher in the PR than in the GR. On multivariate logistic regression analysis, larger PVR, higher OABSS-UUI-score, and the choice of naftopidil were significant risk factors for insufficient improvement of OAB symptoms. CONCLUSIONS: Pre-treatment PVR, UUI severity, and the choice of treatment agent are predicting factors related to OAB improvement after alpha-1 blocker monotherapy in patients with BPH/OAB.

Analysis of continence reflexes by dynamic urethral pressure recordings in a rat stress urinary incontinence model induced by multiple simulated birth traumas.

The present study evaluated real-time changes in urethral pressure during the storage phase using a rat model with stress urinary incontinence (SUI) induced by simulated multiple birth traumas and investigated the relationship between urethral continence function and dynamic parameters associated with the changes in urethral pressure. Sprague-Dawley rats were divided into the following two groups: the sham group, which underwent three catheterizations of the vagina without distension at 2-wk intervals, and the vaginal distension (VD) group, which underwent three VDs at 2-wk intervals. After transection of the T8-T9 spinal cord, simultaneous bladder and urethral pressure recordings were performed during intravesical pressure elevation. Urodynamic parameters such as leak point pressure (LPP), urethral baseline pressure (UBP), maximum urethral pressure (MUP), the MUP-UBP differential (dUP) during intravesical pressure elevation, the bladder pressure when urethral contraction begins (Puc), and the bladder pressure at bladder neck opening (Pno) were then measured and compared. Compared with the sham group, LPP, UBP, dUP, MUP, Puc, and Pno were significantly decreased in the VD group. Pressure differences between LPP and Pno and between LPP and UBP (LPP-UBP) were also significantly different in the two groups. However, difference values of LPP and MUP or Pno and UBP were not altered after VD. Our new methods of simultaneous recordings of dynamic changes in bladder and urethral pressures are useful to fully evaluate the functional alterations in urethral continence function in the SUI model induced by multiple VDs. Moreover, LPP-UBP values, which correspond to the difference between Valsalva LPP and maximum urethral closure pressure in clinical urodynamics, would be useful to evaluate the impaired urethral continence function after simulated birth traumas in animal models.

Urodynamic analysis of the impact of diabetes mellitus on bladder function.

OBJECTIVES: To analyze sequential changes of diabetic cystopathy based on urodynamic data in patients with diabetes mellitus. METHODS: Participants included male diabetes patients who underwent a pressure flow study at Nagoya University Graduate School of Medicine, Nagoya, Japan, from April 2005 to October 2016. Patients with a previous history of lower urinary tract dysfunction were excluded. Bladder dysfunction was categorized into four urodynamic patterns: (i) normal; (ii) detrusor overactivity with normal detrusor contractility; (iii) detrusor hyperreflexia/impaired contractility; and (iv) detrusor underactivity. The urodynamic patterns were evaluated according to the presence of diabetic retinopathy and nephropathy, which was correlated to diabetes mellitus duration. Furthermore, the association of clinical factors with voiding function, as well as sensory function, was investigated. RESULTS: A total of 57 patients were enrolled. Detrusor overactivity with normal detrusor contractility patterns was seen only in cases with neither diabetic retinopathy nor diabetic nephropathy, whereas the prevalence of detrusor hyperreflexia/impaired contractility pattern was highest in cases with diabetic retinopathy. Detrusor underactivity pattern was found with the highest frequency in cases with both diabetic retinopathy and diabetic nephropathy. On multivariate analysis, the existence of diabetic retinopathy was only significantly correlated with bladder contractility index. Furthermore, multivariate analysis showed that first desire volume and maximum cystometric capacity were significantly positively correlated with post-void residual urine volume, and also negatively correlated with voiding efficiency independent of bladder contractility index. CONCLUSIONS: Diabetes patients have diverse progressive bladder dysfunction according to the diabetes stage. An optimal screening program is necessary to detect and manage diabetic cystopathy at an early stage.

Comparison in the efficacy of fesoterodine or mirabegron add-on therapy to silodosin for patients with benign prostatic hyperplasia complicated by overactive bladder: A randomized, prospective trial using urodynamic studies.

AIMS: To compare the efficacy of fesoterodine or mirabegron add-on therapy for persistent overactive bladder (OAB) symptoms despite silodosin monotherapy in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, in both subjective and objective aspects. METHODS: A total of 120 patients with persistent OAB symptoms despite silodosin monotherapy were randomized to receive add-on therapy with fesoterodine (4 mg/day) or mirabegron (50 mg/day) for 12 weeks. At week 12, changes from baseline in patients' subjective symptoms and voiding/storage functions, as assessed using the International Prostate Symptom Score (IPSS), OAB symptom score (OABSS), and urodynamic studies, were compared between the groups. RESULTS: The final analysis included 50 and 52 patients in the fesoterodine and mirabegron groups, respectively. Although the IPSS and OABSS significantly improved in both groups, the fesoterodine (vs mirabegron) group showed significantly greater improvements in the OABSS-total (-2.8 vs -1.5, P = 0.004), IPSS-QOL (-1.5 vs -1.1, P = 0.04), and OABSS-urgency score (-1.5 vs -0.9, P = 0.008) at 12 weeks. Regarding storage functions, although both groups showed significant improvements, the fesoterodine group demonstrated greater improvements in the detrusor overactivity alleviation rate (52.6% vs 28.9%, P = 0.03). Voiding functions did not deteriorate in either group at 12 weeks; no significant inter-group differences were observed. Post-void residual urine significantly increased by 16 mL only in the fesoterodine group. CONCLUSION: Add-on therapy of fesoterodine to silodosin was more effective than adding mirabegron to silodosin for improving OAB symptoms and storage functions, without deteriorating voiding symptoms or functions.

[PRIMARY PROSTATIC RHABDOMYOSARCOMA WITH REPEATING CEREBRAL HEMORRHAGE FROM BRAIN METASTASES IN AN ADULT: A CASE REPORT].

A 28-year-old man visited a nearby doctor with a chief complaint of hematospermia. Magnetic resonance imaging showed a tumor 12-cm in diameter in his pelvis and he was introduced to our hospital. The tumor had replaced the prostate and infiltrated the rectum. He already had multiple lung, pelvic lymph, and bone metastases. He was diagnosed with embryonal rhabdomyosarcoma based on pathological findings after needle tumor biopsy. His disease was stage IV rhabdomyosarcoma according to the Intergroup Rhabdomyosarcoma Study, and he received a VAC (vincristine, actinomycin D, cyclophosphamide) chemotherapy regimen. Despite a partial response with 44% shrinkage in tumor diameter after seven cycles of chemotherapy, he experienced cerebral hemorrhage from small brain metastases during preparation for the eighth course. During gamma knife planning, the cerebral hemorrhage from small brain metastases repeated four times. The patient died 8 months after the introduction of chemotherapy.

Objective impacts of tadalafil on storage and voiding function in male patients with benign prostatic hyperplasia: 1-year outcomes from a prospective urodynamic study.

PURPOSE: To investigate the 1-year effects of tadalafil on storage and voiding function in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH) based on a urodynamic study. METHODS: In a one-armed, prospective study, 105 untreated outpatients with LUTS/BPH received 5 mg tadalafil every day for 12 months. Subjective symptoms and objective findings on voiding and storage functions, obtained through urodynamic studies that included cystometry and pressure flow study, were evaluated before, at 3 months, and at 12 months of treatment. RESULTS: The analysis included 94 patients with a mean age of 70.7 years and a mean prostate volume of 44.5 mL. Subjective symptom parameters of LUTS were significantly ameliorated after 3 months, and progressively improved until study conclusion. Similarly, monitoring of storage and voiding functions revealed significant improvements after 3 months that continued to improve until 12 months. In 49 patients who revealed detrusor overactivity during cystometry at the baseline assessment, uninhibited detrusor contractions disappeared in 15 (30.6%) patients after 3 months (p = 0.02), and in 22 (44.9%) after 12 months (p < 0.001). Mean maximum flow rate significantly increased by 2.9 mL/s during the 12-month treatment (p < 0.001), whereas mean bladder outlet obstruction index significantly decreased from 59.5 at baseline to 45.7 at 3 months (p = 0.001), and to 42.9 at 12 months (p < 0.001). CONCLUSIONS: Tadalafil significantly improved storage and voiding functions, along with LUTS, in patients with LUTS/BPH during a 1-year treatment.

The effect of herpes simplex virus vector-mediated gene therapy of protein phosphatase 1α on bladder overactivity and nociception.

AIMS: We studied the effect of herpes simplex virus (HSV) vectors-based gene transfer of protein phosphatase 1α (PP1α) on bladder hypersensitivity in rats. METHODS: Using adult female Sprague-Dawley rats, non-replicating HSV vectors carrying PP1α or green fluorescent protein (GFP) were injected into the bladder wall. At one week after vector inoculation, cystometry and Western blot assay were performed, whereas the other experiments were performed at 2 weeks after vector inoculation. RESULTS: GFP-expressing cells were identified in the bladder as well as in L6/S1 dorsal root ganglia at 14 days. In cystometry, intercontraction intervals (ICI) after resiniferatoxin (RTx; TRPV1 agonist) irrigation was significantly reduced in the PP1α group in comparison with the GFP group. Moreover, RTx-induced freezing behavior events were observed significantly more frequently in the PP1α group than the GFP group. The number of c-Fos positive cells in the L6 spinal dorsal horn was significantly less in the PP1α group than in the GFP group. Western blot assay revealed lower levels of phosphorylated inositol 1, 4, 5-triphosphate receptor (p-IP3 R), and phosphorylated TRPV1 in the PP1α compared with the GFP group. CONCLUSIONS: HSV vectors-mediated PP1α gene therapy may be an alternative treatment modality for cystitis-related hypersensitive bladder condition at least in part via modulation of the IP3 R signaling pathway.

Treatment of male stress urinary incontinence using autologous adipose-derived regenerative cells: Long-term efficacy and safety.

OBJECTIVES: To investigate the long-term efficacy and safety of periurethral injection of autologous adipose-derived regenerative cells for the treatment of post-prostatectomy stress urinary incontinence. METHODS: A total of 13 patients with persistent stress urinary incontinence after prostate surgery (radical prostatectomy, 10 patients; holmium laser enucleation of the prostate, three patients) underwent periurethral injection of adipose-derived regenerative cells and were followed up for >4 years. A 24-h pad test was carried out for four consecutive days in each evaluation period, and changes in the mean daily leakage volume during the 4 days from baseline to 60 months after treatment were evaluated. RESULTS: The mean follow-up period was 69 months (range 55-72 months). The mean leakage volume/24 h in all patients changed from 260.7 g to 152.7 g. Urinary incontinence progressively improved up to 12 months after treatment in 10 patients, who maintained improvement up to the final assessment, with the mean daily leakage volume decreasing from 281.5 g to 119.0 g (reduction rate 57.7%). The other three patients showed no improvement at 1 year and at the final assessment. After the perioperative period, significant adverse events or prostate-specific antigen increase were not observed during long-term follow up. CONCLUSIONS: The present findings suggest that periurethral injection of autologous adipose-derived regenerative cells is a safe and feasible treatment modality with long-term efficacy for patients with male stress urinary incontinence caused by urethral sphincter deficiency.

Two-year follow up of silodosin on lower urinary tract functions and symptoms in patients with benign prostatic hyperplasia based on prostate size: a prospective investigation using urodynamics.

BACKGROUND: The aim of this research was to investigate intermediate-term effects of silodosin on lower urinary tract functions and symptoms in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) according to prostate size, using urodynamics. METHODS: A total of 70 untreated outpatients with a prostate volume <40 ml [small prostate (SP) group] and 70 with prostate volume ⩾40 ml [large prostate (LP) group] were prospectively enrolled and treated by monotherapy with silodosin for 24 months. Changes in parameters from baseline to 3 months and 24 months after silodosin administration were assessed based on LUTS, voiding and storage function. In addition, withdrawal rates of silodosin due to insufficient effects were compared between the two groups and factors to influence the withdrawal were investigated. RESULTS: The International Prostate Symptom Score (IPSS), bladder outlet obstruction index (BOOI), and detrusor overactivity (DO) improved significantly for the 2-year follow up in both groups as compared with the baseline. IPSS, BOOI and DO improved by 40.4%, 41.3%, and 48.1% in the SP group, 32.7%, 35.9%, and 34.4% in the LP group at 3 months, while, 44.3%, 43.5%, and 63.0% in the SP group, 22.6%, 21.1%, and 34.4% in the LP group at 24 months, respectively. Improvement rates in the IPSS and BOOI at 3 months were maintained until 24 months in the SP group, but decreased in the LP group. Storage function improvements continued in both groups for 2 years. Dropout rate due to unsatisfactory effects was significantly higher in the LP group (20% versus 8.6%). Maximum flow rate, BOOI, and intravesical prostatic protrusion had a significant influence on the withdrawal of silodosin treatment in the LP group. CONCLUSIONS: Silodosin significantly improved lower urinary tract functions for 2 years in patients with LUTS/BPH, regardless of prostate size. However, LUTS and BOO improvements tended to decrease in patients with a large prostate (>40 ml) in the intermediate term.

Effect of TRPV4 activation in a rat model of detrusor underactivity induced by bilateral pelvic nerve crush injury.

AIMS: To produce an animal model of peripheral neurogenic detrusor underactivity (DU) and to evaluate the effect of TRPV4 receptor activation in this DU model. METHODS: In female Sprague-Dawley rats, bilateral pelvic nerve crush (PNC) was performed by using sharp forceps. After 10 days, awake cystometrograms (CMG) were recorded in sham and PNC rats. A TRPV4 agonist (GSK 1016790A) with or without a TRPV4 antagonist (RN1734) were administered intravesically and CMG parameters were compared before and after drug administration in each group. The TRPV4 transcript level in the bladder mucosa and histological changes were also evaluated. RESULTS: In CMG, PNC rats showed significant increases in intercontraction intervals (ICI), number of non-voiding contractions (NVCs), baseline pressure, threshold pressure, bladder capacity, voided volumes, and post-void residual (PVR) compared to sham rats. Contraction amplitude and voiding efficiency were significantly decreased in PNC rats. In PNC rats, intravesical application of GSK1016790A (1.5 µM) significantly decreased ICI, bladder capacity, voided volume, and PVR without increasing NVCs, and these effects were blocked by RN1734 (5.0 µM). In contrast, 1.5 µM GSK1016790A had no significant effects on CMG parameters in normal rats. TRPV4 expression within the bladder mucosa of PNC rats was increased in association with urothelial thickening. CONCLUSIONS: Rats with bilateral PNC showed characteristics of DU, and this model seems appropriate for further evaluation of peripheral neurogenic mechanisms of DU. Also, TRPV4 receptors, the activation of which reduced bladder capacity and PVR, could be a target for DU treatment.

Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury.

NEW FINDINGS: What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. ABSTRACT: Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 µg kg-1  h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast-Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.