Efficacy of acupoint application in patients with overactive bladder: A randomized, placebo-controlled pilot trial.

OBJECTIVE: Conventional treatments for alleviating the symptoms of Overactive bladder (OAB) have been reported to have limited efficacy and a high rate of side effects. Traditional Chinese medicine (TCM) has been used in Asia countries because of its low side effects and being easy to operate. To confirm the efficacy of acupoint application treatment for alleviating OAB symptoms, a randomized and placebo-controlled pilot trial was conducted in this study. METHODS: All participants were randomly allocated into a treatment group or control group, receiving either a "Dinggui" acupoint application or placebo treatment for 4 weeks. The outcome measures were OAB symptom scores (OABSS), OAB questionnaire (OAB-q) scores, and TCM syndrome scores. Urine nerve growth factor (NGF) level, NGF normalized to urine creatinine (NGF/Cr), and maximum flow rate (Qmax) were also measured to evaluate the OAB symptoms. RESULTS: In total, 69 participants were included with 34 in the treatment group and 35 in the placebo-treated group. Treatment with "Dinggui" acupoint application showed a statistically significant decrease in OABSS scores (8.10±1.54 to 3.67±1.77), OAB-q scores (61.43±13.93 to 38.13±15.42), and TCM syndrome scores (15.60±5.98 to 9.20±4.82). The NGF and NGF/Cr were also observed meaningful changes in a decrease from 379.68 to 136.17 pg/ml and from 0.30 to 0.16 pg/mg, respectively. The Qmax value showed a significant increase from 14.40 to 24.05 ml/s. CONCLUSIONS: Treatment with "Dinggui" acupoint application could be considered an effective and alternative therapy for OAB management. Further studies with larger sample sizes and longer treatment periods are needed to investigate.

The surgical effect on overactive bladder symptoms in women with pelvic organ prolapse.

This study aimed to explore the effect of pelvic reconstruction surgery on the relation of pelvic organ prolapse (POP) and overactive bladder (OAB) and the impact of preoperative vaginal oestrogen supplement on vaginal tissue. A total of 100 postmenopausal women with symptomatic POP who underwent pelvic reconstruction surgery (laparoscopic sacrocolpopexy or transvaginal mesh) were enrolled in this study. Preoperative vaginal oestrogen was prescribed in 28 cases. The evaluation tools consisted of POP-Q, urodynamic study, Overactive Bladder Symptom Score (OABSS), and urinary NGF. Vaginal maturation index and vaginal specimens for hormone receptors study were investigated during operation to evaluate the effect of topical oestrogen. Follow-up assessments were performed at 1, 3, and 6 months after surgery. Preoperatively, 58 (58%) were POP with OAB. After reconstruction surgery, the OABSS decreased significantly (6.87 ± 0.85 vs 3.77 ± 0.61, p < 0.001) at postoperative 6 months in the group. Remarkable increasing trends of urinary NGF levels are noted till 3 months postoperatively, then decreasing to the baseline level at 6 months postoperative follow-up. Remarkable decrease of mRNA of the androgen receptor and significant higher expression of progesterone receptor (PR) were noted after use of the vaginal oestrogen cream. The severity of OAB in the POP women shows moderate degree according to OABSS. Pelvic reconstruction surgery can significantly improve the OAB symptoms. The surgery induced inflammation effect lasts for about 6 months. Short-term preoperative supplement of topical oestrogen brings alterations of the vaginal epithelium.

Relationship of Bladder Pain With Clinical and Urinary Markers of Neuroinflammation in Women With Urinary Urgency Without Urinary Incontinence.

PURPOSE: The pathogenesis of bladder pain is poorly understood. Our hypothesis is that in women with urinary urgency without incontinence, bladder pain is associated with the presence of neurogenic inflammation in the bladder wall and neuroinflammatory biomarkers in the urine. METHODS: We conducted a prospective cross-sectional study of women with urinary urgency without incontinence. Urinary symptoms were measured using Female Genitourinary Pain Index. Neuropathic pain, a clinical biomarker of neuroinflammation, was measured using the PainDETECT questionnaire. Inflammatory neuropeptides measured in the urine included nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, and osteopontin. Neuropathic pain scores and urinary neuropeptide levels were compared between patients with and without bladder pain using univariable and multivariable analyses. RESULTS: In 101 women with urinary urgency without incontinence, 62 (61%) were in the bladder pain group (visual analog scale score, ≤ 3), whereas 39 (39%) were in the no bladder pain group. Urinary symptom scores (5.0 ± 3.1 versus 3.5 ± 2.4, P < 0.001) and neuropathic pain scores (13.3 ± 8.6 vs 5.1 ± 4.8, P < 0.001) were significantly higher for the bladder pain group than for the no bladder pain group. On multivariable analysis after controlling for age, body mass index, and severity of urinary urgency, bladder pain score was significantly associated with elevated urinary levels of vascular endothelial growth factor (P = 0.04) and osteopontin (P = 0.02), whereas the neuropathic pain score was significantly associated with an increased NGF level (P = 0.03). CONCLUSIONS: In women with urinary urgency without incontinence, bladder pain is associated with the presence of clinical and urinary biomarkers of neuroinflammation.

Repeated intravesical injections of platelet-rich plasma improve symptoms and alter urinary functional proteins in patients with refractory interstitial cystitis.

Repeated intravesical injections of autologous platelet-rich plasma (PRP) have been shown to improve symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS); however, there is a paucity of objective evidence of the effectiveness of this therapy. In this study, we investigated the changes in urinary markers after PRP treatment. Forty patients with IC/BPS who were refractory to conventional therapy received four injections of PRP at monthly intervals; 10 mL PRP solution with 2.5 times the peripheral blood platelet concentration was used. Urine levels of thirteen functional proteins, growth factors, and cytokines were assessed at baseline and at the 4th PRP injection. The clinical parameters included visual analog scale (VAS) pain score, daily urinary frequency, nocturia episodes, functional bladder capacity, and global response assessment (GRA). The GRA and symptom score significantly decreased post-treatment. In patients with GRA ≥ 2, the success rates at 1 month and at 3 months after the 4th PRP injection were 70.6% and 76.7%, respectively. The VAS pain score, frequency, and nocturia showed a significant decrease (all p < 0.05). Urinary levels of nerve growth factor, matrix metalloproteinase-13, and vascular endothelial growth factor significantly decreased post-treatment (p = 0.043, p = 0.02, and p = 0.000, respectively); platelet-derived growth factor-AB showed a significant increase (p = 0.004) at the 4th PRP treatment compared with baseline. In this study, repeated intravesical PRP injections provided significant symptom improvement in IC/BPS patients with concomitant changes in the related biomarker levels.Trial registration: ClinicalTrial.gov: NCT03104361; IRB: TCGH 105-48-A.

Effect of Water Avoidance Stress on serum and urinary NGF levels in rats: diagnostic and therapeutic implications for BPS/IC patients.

Nerve growth factor (NGF) is thought to play a key role in chronic pain felt by bladder pain syndrome/interstitial cystitis (BPS/IC) patients by activating its high affinity receptor tropomyosin-related kinase subtype A (Trk A). Whether this pathway is also involved in the aggravation of pain sensation during stress events was here investigated. The levels of plasmatic NGF were increased in rats submitted to Water Avoidance Stress test (WAS), compared to controls. The administration of the alpha1A adrenoceptors blocker silodosin prevented the increase of plasmatic NGF. Urinary NGF levels were also moderately increased in animals submitted to WAS. WAS increased pain behaviour score, lowered abdominal mechanical pain threshold and increase voiding bladder reflex activity. These changes were prevented by the administration of TrkA antagonist GW441756. These findings prompt the use of plasmatic NGF as diagnosis tool for chronic visceral painful conditions and opens therapeutic opportunities for TrkA receptors antagonist/NGF sequestration.

The Impact of Chronic Pelvic Ischemia on LUTS and Urinary Levels of Neuroinflammatory, Inflammatory, and Oxidative Stress Markers in Elderly Men: A Case-control Study.

OBJECTIVE: To investigate lower urinary tract symptoms (LUTS) and urinary levels of neuroinflammatory, inflammatory, and oxidative stress markers in elderly men with chronic pelvic ischemia (CPI) caused by significant aortoiliac disease. MATERIALS AND METHODS: Thirteen men aged over 60 years, with aorta, unilateral or bilateral common/internal iliac artery occlusion documented by computed tomography angiography or angiography, were enrolled from the vascular surgery department. Twelve sex- and age-matched controls without significant aortoiliac disease were used for comparison. Exclusion criteria included neurogenic bladder dysfunction, bladder or prostate cancer, prostatic surgery, pelvic radiotherapy, or chronic treatment for LUTS. Participants underwent urological examination, including assessment of International Prostate Symptom Score (IPSS), uroflowmetry, postvoid residual (PVR), and prostate volume. Urine samples were collected, and levels of neuroinflammatory (nerve growth factor, NGF), inflammatory (cytokines), and oxidative stress markers (8-hydroxy-2'-deoxyguanosine) were determined by enzyme-linked immunosorbent assay. RESULTS: Groups were similar for age, PVR, prostate volume, and most cardiovascular risk factors. IPSS was higher in patients with CPI (11 ± 3 vs 8 ± 2, P = .02), with a significant mean difference between groups of three points. Urinary NGF was significantly higher in men with CPI (3.7 ± 0.8 vs 2.9 ± 0.7, P = .02), but no differences were found in inflammatory and oxidative biomarkers among groups. CONCLUSION: Severe CPI in elderly men is associated with a significant increase in LUTS and bladder neurogenic inflammation, as suggested by the increase of NGF release in urine, sensitizing bladder afferents. These findings confirm the relevance of ischemia in bladder function and appear to validate animal models of bilateral iliac artery occlusion.

[Sensitivity and specificity of urinary and serum neurotrophins in the diagnosis of neurogenic detrusor overactivity in multiple sclerosis].

Lower urinary tract dysfunction is common among neurological patients. Traditionally, the basic method of diagnosis is a complex urodynamic study. In recent years, many studies have focused on the search for new non-invasive diagnostic modalities. In particular, neurotrophins are considered as potential biological markers of a neurogenic bladder. AIM: To estimate the sensitivity and specificity of the serum and urinary nerve growth factor (NGF) and brain neurotrophic factor (BDNF) in MS patients as markers of detrusor overactivity. MATERIALS AND METHODS: The study comprised 20 patients with multiple sclerosis, who complained of voiding problems. The control group consisted of 20 people without neurological diseases, lower urinary tract symptoms and detrusor overactivity estimated by filling cystometry. Apart from standard laboratory tests, diagnostic evaluation included a complex urodynamic study, ultrasound of the urinary tract, cystoscopy, testing serum and urinary NGF and BDNF using the enzyme immunoassay. The diagnostic significance of neurotrophins was evaluated using ROC analysis. RESULTS: According to the ROC analysis, the diagnostic sensitivity and specificity of serum NGF as a marker of detrusor hyperactivity was 57% and 93%, respectively (for serum NGF more or equal 26 pg/ml). The quality of the test according to the expert scale of AUC values was "very good" (AUC=0.806). Detecting NGF in patients urine was less effective. The sensitivity and specificity were 52% and 40%, respectively (for NGF more or equal 6 pg/ml). The quality of the test according to the expert scale of AUC values was "average" (AUC=0.64). The serum BDNF demonstrated high sensitivity (90%) and low specificity (23%), AUC=0.56. The urinary BDNF was more informative, (AUC=0.65). The combination of all four markers provides a sensitivity of 85.7% and a specificity of 66.7% (AUC=0.824). CONCLUSIONS: Testing serum and urinary neurotrophins in patients with multiple sclerosis can be used to diagnose detrusor overactivity. The NGF is a highly specific biomarker, while the BDNF is highly sensitive. Combined testing for serum NGF and BDNF is most informative.

Nerve Growth Factor Levels are Associated with Overactive Bladder Symptoms and Long-Term Treatment Outcome after Transurethral Resection of the Prostate in Patients with Benign Prostatic Hyperplasia.

PURPOSE: We investigated changes in urinary nerve growth factor in patients with benign prostatic hyperplasia after transurethral prostate resection. We also assessed the association between nerve growth factor and changes of overactive bladder symptoms and long-term treatment outcomes after surgery. MATERIALS AND METHODS: This was a prospective study of 178 patients at Peking University People's Hospital with benign prostatic hyperplasia between January 2011 and January 2013. Urinary nerve growth factor levels were determined preoperatively using a commercial enzyme-linked immunosorbent assay kit. We also determined prostate volume, I-PSS (International Prostate Symptom Score), quality of life, OABSS (Overactive Bladder Symptom Score), ultrasound estimated post-void residual urine and urodynamics before surgery. Urinary nerve growth factor levels, I-PSS and OABSS were assessed again 1 year after transurethral prostate resection. RESULTS: Urinary nerve growth factor/creatinine levels differed between patients with moderate and severe lower urinary tract symptoms (mean ± SD 10.513 ± 4.255 vs 12.334 ± 4.048 pg/µmol, p = 0.002). There was no significant difference between patients with grades III/IV and V/VI bladder outlet obstruction (mean 11.285 ± 4.069 vs 11.781 ± 4.437 pg/µmol, p = 0.354). However, differences were significant for urinary nerve growth factor/creatinine levels in patients without overactive bladder, and mild, moderate and severe overactive bladder (mean 8.132 ± 3.489, 10.128 ± 3.817, 13.232 ± 3.290 and 14.029 ± 3.820 pg/µmol, respectively, p <0.001). One year after transurethral prostate resection we noted a decrease vs baseline in mean urinary nerve growth factor/creatinine (8.978 ± 4.022 pg/µmol, p <0.001), and I-PSS and OABSS (10.2 ± 5.4 and 4.3 ± 3.7, respectively, each p <0.001). Compared with the good outcome group, the fair/poor group had higher mean baseline urinary nerve growth factor/creatinine (12.319 ± 4.017 vs 11.015 ± 4.298 pg/µmol, p = 0.045), higher mean 1-year urinary nerve growth factor/creatinine (10.847 ± 4.267 vs 7.850 ± 3.419 pg/µmol, p <0.001) and a lesser mean postoperative change in urinary nerve growth factor/creatinine (1.472 ± 4.928 vs 3.165 ± 4.863 pg/µmol, p = 0.031). CONCLUSIONS: Nerve growth factor was associated with overactive bladder symptoms in patients with benign prostatic hyperplasia as well as with the assessment of successful long-term treatment outcome of bladder outlet obstruction with symptoms of overactive bladder.

Urine nerve growth factor (NGF) level, bladder nerve staining and symptom/problem scores in patients with interstitial cystitis.

BACKGROUND: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a challenging disease, affecting thousands of people all around the world, especially women. Although there have been numerous theories regarding IC/BPS etiology, the physiopathology of the disease still remains unclear and there is a lack of certain treatment. OBJECTIVES: The aim of the study was to assess the role of nerve fibers and nerve growth factor (NGF) in the etiopathogenesis of IC/BPS symptoms by demonstrating if there is a correlation between urine NGF levels, amount of peripheral nerves in bladder mucosa and symptom severity. MATERIAL AND METHODS: A prospective clinical study was conducted with 15 IC/BPS patients and 18 controls. Urine NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Bladder punch biopsies were obtained from 15 IC/BPS patients and 9 controls. Immunohistochemistry was performed for S-100 to highlight peripheral nerve twigs in bladder mucosa. The O'Leary-Sant Interstitial Cystitis Symptom and Problem Index (OSICSPI) was used to assess symptom severity and effects of the disease on the patients' life. RESULTS: NGF normalized to urine creatinine (NGF/Cr) levels in IC/BPS patients were significantly higher than in controls, 0.34 ±0.22 and 0.09 ±0.08 pg/mL: mg/dL, respectively (p < 0.001). The mean symptom score in IC patients was 12.27 ±2.4 (median: 12) and the mean problem score was 10.9 ±2.3 (median: 12). The mean mucosal nerve (S-100 stained) area in the IC/BPS group was significantly higher than in the controls, 2.53 ±1.90 vs 1.0 ±0.70, respectively (p = 0.018). In correlation analyses, the NGF/Cr level in IC/BPS patients was found significantly correlated with the O'Leary-Sant IC Symptom and Problem Index scores independently (p = 0.001 and p = 0.028, respectively). CONCLUSIONS: NGF seems to be a promising biomarker in IC/BPS. It may help clinicians in diagnoses and patient follow-up. Thus, unnecessary, expensive and invasive tests, interventions and treatments might be avoided.

MicroRNAs as potential biomarkers to predict the risk of urinary retention following intradetrusor onabotulinumtoxin-A injection.

AIMS: MicroRNAs (miRs) control post-transcriptional gene expression, and this is relevant in understanding better chronic diseases and treatment outcomes. The role of miRs in the pathology and treatment outcomes of overactive bladder (OAB) is unknown. In this study, we assessed the differential expression of miRs in OAB patients responding with either normal or elevated post-void residual volumes (PVRs) ≥200 mL following intradetrusor injection of onabotulinumtoxin-A (onaBoNT-A). METHODS: Female OAB patients refractory to OAB drugs were consented for this study. Cystoscopic-guided punch bladder biopsy was obtained at the time of injection of onaBoNT-A 100 units. The expression of 13 miR species, selected for their known effect on neurotrophin expression and smooth muscle function, was measured. PVRs and urine nerve growth factor (NGF) levels were measured at baseline and at the follow-up visit. RESULTS: Fourteen patients with mean age of 66 years were consented. Of these patients, nine maintained PVRs <200 mL after onaBoNT-A injection to comprise the low PVR group. The other five patients with PVRs ≥200 mL comprised the high PVR group. The expression of miR221 and miR125b was upregulated by 11- and 2-fold, respectively, in patients who responded with low PVRs after onaBoNT-A (P < 0.05). Urine NGF levels at baseline were not different between the two groups. CONCLUSIONS: This study suggests that deficiency in the pretreatment expression of miR221 and miR125b may predispose OAB patients to high PVRs following intradetrusor onaBoNT-A. Additional studies are needed to better understand the role of miRs in OAB.

The effect of intradetrusor botulinum neurotoxin type A on urinary NGF, TGF BETA-1, TIMP-2 levels in children with neurogenic detrusor overactivity due to myelodysplasia.

AIMS: The aim of this study was to determine the value of urine nerve growth factor (NGF), transforming growth factor beta 1 (TGF-Beta-1), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) levels to predict the urodynamic profile before and after botulinum neurotoxin type A (BoNT-A) treatment in children with myelodysplasia. METHODS: This prospective study included 15 children with myelodysplasia who underwent intradetrusor BoNT-A injections due to neurogenic detrusor overactivity (NDOA). Urine samples of each child were collected before and after BoNT-A injections, specifically at the first and third postoperative months. Urine samples were analyzed with ELISA method and NGF, TGF-Beta-1, and TIMP-2 levels were measured. Urine marker levels and clinical findings were assessed for statistical significance with Wilcoxon Signed Ranks Test and Friedman Test. RESULTS: A total of 15 children (5 boys and 10 girls) were assigned as the study group. Mean age of the patients was 7.1 ± 2.5 years (range 2.5-11). A statistically significantly decline was observed in urinary TGF-Beta-1 and NGF levels following BoNT-A injections, compared to the preoperative levels (P < 0.05). TIMP-2 levels also tend to decrease following BoNT-A injections but this was not statistically significant compared to the preoperative levels. CONCLUSION: This preliminary study, suggests urinary TGF-Beta-1 and NGF as a potent marker in children with NDOA, as they decline following BoNT-A injection. Further studies are needed in identifying their special role in assessing treatment success after invasive interventions.

Could urinary nerve growth factor be a biomarker for overactive bladder? A meta-analysis.

OBJECTIVE: The previously reported association between urinary nerve growth factor (NGF) and overactive bladder (OAB) was controversial. We performed this meta-analysis based on current available studies to sum up all evidence on this association. METHODS: Studies were identified by searching PubMed, Embase, and Cochrane library from inception to September 2016. Pooled standardized mean difference (SMD) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: A total of 17 published studies were included in this meta-analysis. Among the studies considered, patients with OAB had a significant higher baseline urinary NGF/Cr (NGF normalized to urine creatinine) level compared to those of controls (SMD = 0.74, 95%CI = 0.43-1.04, P < 0.00001). After treatment, the level of NGF/Cr decreased significantly in OAB group. However, there was no significant difference between patients with IC (interstitial cystitis)/PBS (painful bladder syndrome) and patients with overactive bladder (OAB) with regard to the urinary NGF/Cr level (SMD = 0.18, 95%CI = -0.06 to 0.41, P = 0.14). There was a statistically significant heterogeneity among included studies (P < 0.00001, I2 = 85%). No obvious evidence of significant publication bias was detected. In conclusion, this meta-analysis indicates that urine NGF/Cr may be a useful biomarker for OAB in the future. Because of lack of specificity, it seems that NGF/Cr cannot be used as a biomarker for OAB at present. Nevertheless, combined with other biological indicators may improve its specificity in diagnosis. More high quality studies that control the compounding factors strictly should be conducted in the future.

Urinary neurotrophic peptides in postmenopausal women with and without overactive bladder.

AIMS: The aim of this study was to compare the expression of urinary nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), substance P (SP), and calcitonin-gene related peptide (CGRP) in women with and without overactive bladder (OAB). We sought to determine factors associated with higher expression of these neuropeptides. METHODS: Participants with OAB and age-matched controls were enrolled. Symptom severity was assessed with validated questionnaires. Urinary neurotrophin levels, symptom scores, and clinical data were compared between the groups. Multivariate analysis determined independent factors associated with urinary neurotrophin levels. RESULTS: Sixty-seven women (38 OAB, 29 controls) were included. Women with OAB and controls were similar in age, race, body mass index, parity, and smoking status. Women with OAB were more likely to report a history of pelvic pain and pelvic surgery. Neurotrophic factor levels normalized to urinary creatinine did not differ between the groups. Increasing age was associated with greater urinary levels of BDNF and NGF (ß = 0.23, 95%CI 0.11-0.34 and 0.75, 95%CI 0.17-1.33, respectively, P < 0.02). Higher urinary NGF was associated with increasing BMI (ß = 0.81, 95%CI 0.05-1.57, P = 0.04) while pain was associated with elevated urinary SP (ß = 0.21, 95%CI 0.09-0.33, P = 0.001). CONCLUSIONS: Our data does not support a relationship between urinary neurotrophin levels and OAB in age-matched postmenopausal women. Further research is necessary to elucidate the role of urinary neurotrophins in the diagnosis and management of OAB. Neurourol. Urodynam. 36:740-744, 2017. © 2016 Wiley Periodicals, Inc.

Urinary Neurotrophin Levels Increase in Women With Stress Urinary Incontinence After a Midurethral Sling Procedure.

OBJECTIVE: To investigate the association between urinary neurotrophin levels, maximum flow rate (Qmax) variation, and the appearance of urgency in women with stress urinary incontinence (SUI) after a midurethral sling (MUS) procedure. MATERIALS AND METHODS: Thirty-one women with SUI were treated with a MUS. One year later, the outcome of surgery and the onset of urgency were assessed. At baseline and 1-year follow-up, urine was collected to measure nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentration, and Qmax variation was calculated. Urine samples from healthy women (n = 20) without lower urinary tract symptoms and overactive bladder (OAB) wet patients (n = 32) were used as controls. Urinary neurotrophin levels were measured by enzyme-linked immunosorbent assay and normalized to creatinine concentration. RESULTS: At baseline, urinary levels of NGF and BDNF were similar between SUI and healthy women (NGF: 2.10 ± 0.68 vs 1.99 ± 1.05; BDNF: 1.99 ± 0.71 vs 1.81 ± 0.90), and significantly inferior to OAB wet patients (NGF: 2.10 ± 0.68 vs 2.50 ± 0.54, P < .05; BDNF: 1.99 ± 0.71 vs 2.71 ± 0.45, P < .05). After surgery, there was a significant increase of both neurotrophins (vs baseline, P < .05) to the values of OAB wet patients. Moreover, there was a significantly higher percentage increase of NGF in women with de novo urgency than in those without lower urinary tract symptoms (P = .019). A trend for a higher mean Qmax reduction in women with de novo urgency was also found (P = .085). CONCLUSION: These findings suggest that increased bladder outlet resistance after a MUS may play a key role in the rise of urinary neurotrophins, promoting sensitization of bladder primary afferents and causing de novo urgency in susceptible patients.

Measurements of C-reactive protein (CRP) and nerve-growth-factor (NGF) concentrations in serum and urine samples of dogs with neurologic disorders.

BACKGROUND: The purpose of this study was to prove the hypothesis that C-reactive protein (CRP) and nerve growth factor (NGF) may be potential biomarkers for lower urinary tract disorders and may be able to distinguish between micturition dysfunctions of different origin in dogs with spinal cord diseases. NGF- and CRP- concentrations were measured in serum and urine samples using specific ELISA-Kits. Results in urine were standardized by urine-creatinine levels. RESULTS: CRP in serum was detectable in 32/76 and in urine samples in 40/76 patients. NGF could be measured in all serum and in 70/76 urine samples. Urinary CRP concentrations were significantly higher in dogs with micturition dysfunction (p = 0.0009) and in dogs with different neurological diseases (p = 0.0020) compared to the control group. However, comparing dogs with spinal cord disorders with and without associated micturition dysfunction no significant difference could be detected for NGF and CRP values in urine or serum samples. Additionally, levels did not decrease significantly, when measured at the time when the dogs regained the ability to urinate properly (urinary NGF p = 0.7962; urinary CRP p = 0.078). Urine samples with bacteria and/or leukocytes had no significant increase in urinary NGF (p = 0.1112) or CRP (p = 0.0534) concentrations, but higher CRP-levels in urine from dogs with cystitis were found compared to dogs without signs of cystitis. CONCLUSIONS: From these data we conclude that neither CRP nor NGF in urine or serum can be considered as reliable biomarkers for micturition disorders in dogs with spinal cord disorders in a clinical setting, but their production might be part of the pathogenesis of such disorders. Significantly higher levels of CRP could be found in the urine of dogs with micturition dysfunctions compared to control dogs. This phenomenon could potentially be explained by unspecific extrahepatic CRP production by smooth muscle cells in the dilated bladder.

The role of urinary nerve growth factor for the diagnosis and assessment of the biofeedback success in children with dysfunctional voiding.

INTRODUCTION: Dysfunctional voiding (DV) occurs in neurologically normal children who are not able to establish brain control on detrusor muscle contractions (DMCs). It is also reported to be the result of incorrect voiding habits during toilet training. Children contract pelvic floor muscles (PFMs) to suppress DMC and DV begins. Urinary nerve growth factor (uNGF) is necessary for the synthesis and regulation of neurotransmitters, development of dorsal root ganglia (sensory neurons), and development of sympathetic cells during embryonic and post-natal life. uNGF has also a role in the intracellular signal transduction in nerve cells towards the target organ. To our knowledge, no study has investigated the association between uNGF, biofeedback treatment and DV in children. OBJECTIVES: The aim was to examine the potential effect of uNGF in the assessment of the effectiveness of biofeedback success in children with lower urinary tract disorders. STUDY DESIGN: Fifty-two children with the suspicion of DV and 48 children from a primary school reporting no urinary complaints were enrolled in this study from October 2010 to April 2013 in the Urology Department. uNGF levels were compared. RESULTS: The mean uNGF/creatinine (Cr) level was 0.23 ± 0.26 in the control group and 0.96 ± 0.88 in the DV group (p < 0.001). The mean uNGF/Cr levels in the DV group at baseline and at the end of biofeedback therapy at 6 and 12 months were 0.90 ± 0.78, 0.26 ± 0.32, and 0.40 ± 0.50, respectively (p < 0.001) (Figure). DISCUSSION: To our knowledge this study is the first to show the correlations between uNGF levels and biofeedback therapy in children with DV. Tissue NGF in 12 patients with overactive bladder (OAB)/detrusor overactivity and 15 healthy women was previously compared and it was suggested that there was no correlation between bladder tissue NGF and OAB. uNGF levels in the bladder in patients with interstitial cystitis and idiopathic sensorial urgency were evaluated previously, and uNGF levels reported. Similar to these reports, most of the previous studies handled uNGF in patients with diseases such as interstitial cystitis, OAB, urinary tract infections, urolithiasis, spinal cord injury, and prostate cancer, and found significantly higher uNGF levels. These studies were generally in adults. A previous study about uNGF comprised 40 children with OAB, in contrast to other studies. According to this study, 40 children diagnosed with OAB were administered anti-muscarinic therapy (oxybutynin 0.3-0.5 mg/kg/day). It was reported that uNGF/Cr levels of the OAB group were higher than control group. In the current study, we evaluated the uNGF difference in DV and the effect of biofeedback treatment on uNGF levels. CONCLUSIONS: uNGF levels were higher in children with DV and decreased after biofeedback therapy. uNGF levels could be used for the diagnosis and the assessment of biofeedback success in these children.

Effect of silodosin, a selective α(1A)-adrenoceptor antagonist, on voiding behavior and bladder blood flow in a rat model of bladder outlet obstruction.

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

Urinary nerve growth factor in patients with detrusor overactivity.

BACKGROUND: Detrusor overactivity (DO) is one of the most frequent bladder dysfunctions in children up to the age of 18. Nowadays, the only way to confirm DO is by urodynamic investigation, which is an invasive procedure. Among the many mediators influencing bladder function, nerve growth factor (NGF) plays an important role. The present study was designed to measure urinary NGF (uNGF) levels in patients with DO diagnosed by urodynamic study in comparison with healthy controls. METHODS: The investigation was conducted on 44 children, divided into two groups (24 patients with DO, 20 healthy children). Uroflowmetry was performed in all enrolled to the study and cystometry only to patients. uNGF levels were estimated in both studied groups. RESULTS: The median uNGF level in patients with DO before treatment was higher compared with healthy controls. There were no differences between uNGF levels in patients after anticholinergic treatment and the controls. We found differences in uroflowmetry parameters between the reference group and the patients. We found correlations between uroflowmetry parameters and uNGF/cr. level. CONCLUSIONS: 1. The uNGF level could be used for detecting DO in children and adolescents. 2. Measuring uNGF level is a simple, noninvasive procedure and very useful for choosing therapy in patients with DO in various clinical conditions.

The association of urinary nerve growth factor levels with bladder outlet obstruction in women.

OBJECTIVES: Nerve growth factor (NGF) has been proposed as a urinary biomarker and previously shown to be elevated in male patients with bladder outlet obstruction (BOO) and other lower urinary tract symptoms. No published studies have examined NGF as a potential urinary biomarker in women with BOO. The aims of this prospective study were to evaluate NGF levels in urine from women with anatomic BOO resulting from pelvic organ prolapse (POP) and/or previous incontinence surgery and to measure the effect associated with surgical or conservative management. METHODS: From January to September 2012, all female patients referred for evaluation and management of BOO from POP or previous incontinence surgery were screened for enrollment. Inclusion criteria included elevated postvoid residual, valsalva voiding on urodynamics, or urinary peak flow (Qmax) of 12 mL/s or less. A control group of 10 asymptomatic age-matched female volunteers was also recruited. In all subjects, urinary NGF and creatinine (Cr) levels were measured and normalized to the urinary Cr concentrations (NGF/Cr). Urinary NGF levels were measured at 1 month and 3 months after either surgical correction or initiation of clean intermittent catheterization. RESULTS: A total of 10 female patients with anatomic BOO (mean [SD] age of 66.2 [3.88] years) and 10 female control subjects (mean [SD] age of 62 [7] years) were recruited. Nine patients had POP. Six patients had undergone a previous anti-incontinence procedure. Five patients had both POP and undergone a previous anti-incontinence procedure. The urinary NGF/Cr levels in the study patients with BOO (mean [SE] 20.8 [4.31] pg/mg) were significantly higher (P = 0.0001) than the levels in the age-matched control group (5.6 [0.65] pg/mg). After treatment, the urinary NGF/Cr level significantly decreased to 6.50 (0.57) pg/mg (P = 0.01) CONCLUSIONS: In this study, female patients with anatomic BOO resulting from POP and/or previous incontinence surgery had significantly higher urinary NGF/Cr levels when compared with age-matched controls. After treatment, the urinary NGF/Cr levels significantly decreased.