External Urethral Sphincter Research Articles

MP52-15 EXTERNAL URETHRAL SPHINCTER BOTULINUM TOXIN INJECTION TO TREAT PSEUDODYSSYNERGIA IN PATIENTS WITH CEREBRAL PALSY

You have accessJournal of UrologyCME1 Apr 2023MP52-15 EXTERNAL URETHRAL SPHINCTER BOTULINUM TOXIN INJECTION TO TREAT PSEUDODYSSYNERGIA IN PATIENTS WITH CEREBRAL PALSY Ryan Haggart, Christopher J Loftus, Molly DeWitt-Foy, Valencia Henry, Joseph Pariser, and Sean Elliott Ryan HaggartRyan Haggart More articles by this author , Christopher J LoftusChristopher J Loftus More articles by this author , Molly DeWitt-FoyMolly DeWitt-Foy More articles by this author , Valencia HenryValencia Henry More articles by this author , Joseph PariserJoseph Pariser More articles by this author , and Sean ElliottSean Elliott More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cerebral palsy (CP) is an upper motor neuron disorder that typically results in spasticity of striated muscle, which can include the external urinary sphincter. Symptomatic urinary dysfunction in the form of intermittent retention and flooding may result from tonic spasticity of the external urinary sphincter (pseudodyssynergia). Botulinum toxin (BTX) may be injected to the external urinary sphincter to allow for more facile, regular voiding. In the only study examining the use of sphincter BTX injections, a reduction in chronic catheter dependence and urinary tract infection (UTI) rates in the 15 patients studied was reported. The objective of this study is to evaluate urinary outcomes following cystoscopic external urinary sphincter BTX injections in patients with CP. METHODS: In this retrospective cohort study, we reviewed patients with a diagnosis of CP seen in urology clinic from 2016-2022. Patients included were 18 years or older and had undergone a urethral external sphincter BTX injection. Injections were performed with either 100 units or 200 units in 4 cc of saline injected to the anterolateral external urethral sphincter. Data was collected via chart review and entered into a REDCap database. Outcomes included: retention, lower urinary tract symptoms (LUTS), hydronephrosis, and recurrent UTIs recorded as better, no change, or worse based on caregiver or patient feedback and repeat imaging. Urodynamics was performed pre-BTX but often not repeated as many patients are unable to void on command so a proper voiding phase could not be captured. RESULTS: 37 patients met inclusion criteria. The median age was 29 years (IQR 25-39), 57% were male, most (54%) lived at home with or without assistance, and 30% resided in a group home. Prior to BTX, most used a combination of a toilet (59%) and diapers (59%) for bladder management. The most common indication for BTX was retention (92%), followed by LUTS (38%), hydronephrosis (24%), and recurrent UTIs (22%). Post-BTX subjective improvement was seen in 71% (24/34) of patients with retention, 79% (11/14) with LUTS, 75% (6/8) with recurrent UTIs, and 78% (7/9) with hydronephrosis. The majority (68%) of patients underwent repeat injections, typically every 3-6 months. There were no significant complications associated with injections. CONCLUSIONS: External urethral sphincter BTX is a safe, effective option for treating urinary dysfunction in adults with CP. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e708 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryan Haggart More articles by this author Christopher J Loftus More articles by this author Molly DeWitt-Foy More articles by this author Valencia Henry More articles by this author Joseph Pariser More articles by this author Sean Elliott More articles by this author Expand All Advertisement PDF downloadLoading ...

MP60-13 VIRAL TRANSDUCTION EFFICACY OF PERIPHERAL NEURONS INNERVATING THE EXTERNAL URETHRAL SPHINCTER BY LOCAL INJECTION OF ADENO-ASSOCIATED VIRUS VECTORS

You have accessJournal of UrologyCME1 Apr 2023MP60-13 VIRAL TRANSDUCTION EFFICACY OF PERIPHERAL NEURONS INNERVATING THE EXTERNAL URETHRAL SPHINCTER BY LOCAL INJECTION OF ADENO-ASSOCIATED VIRUS VECTORS Firoj Alom, Richard Johnson, and Aaron Mickle Firoj AlomFiroj Alom More articles by this author , Richard JohnsonRichard Johnson More articles by this author , and Aaron MickleAaron Mickle More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Incomplete functional recovery of the lower urinary tract, including the external urethral sphincter (EUS), frequently occurs in spinal cord injury patients. Electrical neuromodulation of the lower urinary tract remains an attractive therapeutic target, but it has yet to be fully deployed clinically. The wide distribution of sensory and motor axons in the pudendal nerve innervating targets in the lower urinary tract but also other targets in other pelvic structures significantly limits the development of electrical neuromodulation strategies. We can address this limitation by using optogenetic techniques to modulate the lower urinary tract using light stimulation. First, we need to determine the viral vectors' efficiency and potential promoters to transduce the specific neuronal populations through local injection into regions of the lower urinary tract. In this study, we investigated the transduction efficiency of adeno-associated virus serotypes in the peripheral regions by local injection into the external urethral sphincter. METHODS: We injected different AAV vector serotypes along with a neural tracer into the external sphincter of rats. After five weeks, we evaluated the viral transduction efficiency of these AAV serotypes. RESULTS: We observed variable transduction of multiple peripheral neuron populations and showed different efficacies of neuronal transduction by these viruses compared with labeling with a neural tracer. We also found that this level of expression by local injection is also relevant for optogenetic-mediated modulation of the EUS function. CONCLUSIONS: Our preliminary results indicate that by using adeno-associated viruses, it is possible to transduce the neurons controlling the EUS by local injection. We think these studies will potentially help improve the viral targeting of neurons controlling lower urinary tract function. Source of Funding: This research was supported by the NIH NIBIB Trailblazer award (R21 EB031249) and in part by the Urology Care Foundation Research Scholar Award Program and Indian American Urological Association Sakti Das, MD Award © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e848 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Firoj Alom More articles by this author Richard Johnson More articles by this author Aaron Mickle More articles by this author Expand All Advertisement PDF downloadLoading ...

PD23-10 REAL-TIME MRI REVEALS A CHANGE IN PROSTATIC URETHRAL ANGLE DURING VOIDING

You have accessJournal of UrologyCME1 Apr 2023PD23-10 REAL-TIME MRI REVEALS A CHANGE IN PROSTATIC URETHRAL ANGLE DURING VOIDING Cody Johnson, Juan P. Gonzalez-Pereira, Labib Shahid, Maxwell Kounga, Shane Wells, Wade Bushman, and Alejandro Roldan-Alzate Cody JohnsonCody Johnson More articles by this author , Juan P. Gonzalez-PereiraJuan P. Gonzalez-Pereira More articles by this author , Labib ShahidLabib Shahid More articles by this author , Maxwell KoungaMaxwell Kounga More articles by this author , Shane WellsShane Wells More articles by this author , Wade BushmanWade Bushman More articles by this author , and Alejandro Roldan-AlzateAlejandro Roldan-Alzate More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003296.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Dynamic changes in urethral anatomy during voiding have never been quantitatively assessed. We used real-time magnetic resonance imaging (MRI) to obtain dynamic, high-fidelity 3D images of the lower urinary tract during voiding. These were then used to create accurate real-time urethral reconstructions throughput the voiding event coupled with determinations of urine flow, pressure and wall shear stress by computational fluid dynamics (CFD). METHODS: MRI scans were performed on a healthy young man using a clinical 3T scanner according to an IRB-approved protocol to acquire a 3D image every 3.7 s during voiding. 3D models of the urethral lumen were created using MIMICS (Materialise, Leuven, Belgium). RESULTS: Diameters of the internal and external urethral sphincter (IUS, EUS) and prostatic urethral angle (PUA) were obtained throughout voiding. CFD, using computational software to model and simulate fluid behavior under specified constraints of geometry and flow, was used to determine wall shear stress (WSS), pressures and fluid velocities along the length of the urethra during maximum flow (Figure 1). IUS diameter remains unchanged throughout voiding whereas EUS diameter correlates positively with urine flow rate (data not shown here). Most notably, we noted a striking change in PUA during voiding. PUA becomes less acute as flow increases, being straightest at peak flow rate (Figure 2). CONCLUSIONS: Real-time MRI can be used to define the biomechanics of the urethra during voiding and reveals – for the first time – a change in prostatic urethral angle during voiding that correlates with urinary flow rate. Source of Funding: NIH: R01 DK126850-01 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e675 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cody Johnson More articles by this author Juan P. Gonzalez-Pereira More articles by this author Labib Shahid More articles by this author Maxwell Kounga More articles by this author Shane Wells More articles by this author Wade Bushman More articles by this author Alejandro Roldan-Alzate More articles by this author Expand All Advertisement PDF downloadLoading ...

Pelvic Floor Muscle Training for Urinary Incontinence After Radical Prostatectomy: A Narrative Review.

Rehabilitative treatment of urinary incontinence after prostatectomy has showed, on the basis of recent published evidence, encouraging results. At first, clinician applied evaluation and treatment approach suggested based on the studies and rationale of female stress urinary incontinence, but although long term literature suggested no evidence of benefits. Recent studies that have shown the real control mechanisms in male continence through the use of trans-perineal ultrasound, demonstrated that it is not appropriate to transfer the rehabilitation techniques applied in female stress incontinence to male incontinence after prostatectomy. Even that pathophysiology of urinary incontinence after prostatectomy is not fully understood, it's in part attributable to a urethral or bladder source. In particular, however, urethral sphincter dysfunction is predominant, secondary to surgical damage and to the partly organic and partly functional dysfunction of the external urethral sphincter; complementary action of all the muscles capable of contributing to the maintenance of urethral resistance is therefore important. As for rehabilitative approach to post-prostatectomy incontinence, the primary objective is to quantify the residual capacity of the muscular function that must replace the sphincter function, often compromised by surgery. Than a multimodal approach, comprising exercise and instrumental therapies, is needed. The present paper's aim was to overview current urinary dysfunction knowledge for male with radical prostatectomy, and to describe practical issue of evaluation and conservative treatment.

The Maximal Urethral Pressure at Rest and during Normal Bladder Filling Is Only Determined by the Activity of the Urethral Smooth Musculature in the Female

The aim of this opinion paper is to determine the entities that define the maximal urethral pressure (MUP) during rest and during bladder filling that is needed to guarantee continence in females. For the development of this opinion, the literature was searched for via the Pubmed database and historic sources. Animal studies indicate that the maximal urethral pressure is determined by the smooth muscle activity in the mid-urethra. Additionally, during increased smooth muscle tone development, the largest sympathetic responses are found in the middle part of the urethra. This could be confirmed in human studies that are unable to find striated EMG activity in this area. Moreover, the external urethral striated sphincter is situated at the distal urethra, which is not the area with the highest pressure. The external urethral sphincter only provides additional urethral pressure in situations of exertion and physical activity. From a physics point of view, the phasic pressure of the external striated sphincter at the distal urethra cannot be added to the tonic pressure generated by the smooth muscle in the mid-urethra. The assertion that mid-urethral pressure is the result of different pressure forces around the urethra, including that of the external striated sphincter, is not supported by basic research evidence combined with physical calculation and should therefore be considered a misconception in the field of functional urology.

Upregulated 5-HT1A Receptors Regulate Lower Urinary Tract Function in Rats after Complete Spinal Cord Injury.

Spinal cord injury (SCI) above the lumbosacral level often leads to dysfunction of the lower urinary tract (LUT) including detrusor hyper-reflexia, wherein bladder compliance is low, baseline pressures are increased, and filling is accompanied by numerous non-voiding contractions (NVCs) referred to as neurogenic detrusor overactivity. Here, we investigate the expression levels of the serotonin 1A (5-HT1A) receptor in segments both rostral and caudal to the injured site, as well as the effects on micturition of blocking 5-HT1A receptor using pharmacological interventions in spinally intact rats or T8 complete SCI rats. The activities of detrusor and external urethral sphincter (EUS) were assessed with the rats in a conscious condition. Adult female rats were divided into two groups: (1) sham control (T8 laminectomy only) and (2) T8 complete spinal cord transection. The observation period was 2 months after the original SCI. In Western blot analyses, we identified significant upregulation of the 5-HT1A receptor in the T10-L2 and L6/S1 segments after chronic complete SCI. In pharmacological studies, a dose-response study of the 5-HT1A receptor antagonist, WAY100635, indicated alterations in detrusor and EUS activities in spinally intact rats. Interestingly, blocking the 5-HT1A receptor alone resulted in inhibitory effects on NVCs with a reduced number and decreased amplitude, but in an increased interval between NVCs in SCI rats. In addition, the duration of EUS bursting was also significantly increased by WAY100635. These inhibitory effects of WAY100635 on NVCs were diminished by subsequent application of a beta-adrenergic blocker (propranolol). The reduction of NVCs observed by WAY100635 may be the result of blocking the constitutive activities of the 5-HT1A receptor but activating the beta-adrenergic sympathetic pathway, which in turn relaxes bladder activity. Together, the neuroplasticity of the 5-HT1A receptor can be a potential therapeutic target for treatment of bladder dysfunction after SCI.

Motor-evoked potential monitoring from urinary sphincter muscle during pediatric untethering surgery: a case series.

Postoperative urinary dysfunction following untethering surgery for spinal lipoma is devastating. To assess urinary function, we invented a pediatric urinary catheter equipped with electrodes for the direct transurethral recording of myogenic potential from the external urethral sphincter (EUS). This paper presents two cases in which urinary function was monitored intraoperatively by recording of motor-evoked potential (MEP) from EUS during untethering surgery in children. Two children (aged 2 and 6years) were included in this study. One patient had no preoperative neurological dysfunction, while the other had frequent urination and urinary incontinence. A pair of surface electrodes was attached to a silicone rubber urethral catheter (6 or 8 Fr; diameter, 2 or 2.6mm). The MEP from the EUS was recorded to assess the function of the centrifugal tract from the motor cortex to the pudendal nerve. Baseline MEP waveforms from the EUS were successfully recorded with latency and amplitude of 39.5ms and 66µV in patient 1 and 39.0ms and 113µV in patient 2, respectively. A significant decrease in amplitude was not observed during surgery in the two cases. No new urinary dysfunction and complications associated with the urinary catheter-equipped electrodes developed postoperatively. Using an electrode-equipped urinary catheter, monitoring of MEP from the EUS could be applicable during untethering surgery in pediatric patients.

Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model.

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague-Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI.

Retrospective Cohort Trial of the Effectiveness of Plasma Surgery for Benign Prostatic Hyperplasia of Large and Giant Sizes

Background. Over the past 10 years, the incidence of benign prostatic hyperplasia (BPH) over 80 cm3 has increased 34 times. With indications for surgical treatment, transurethral methods are increasingly used today with the use of laser or plasma techniques for resection and enucleation of the prostate. The article presents a comparative analysis of the results of plasma transurethral enucleation of the prostate (P-TUEP) and open prostatectomy, methods of surgical and drug prevention of dysuric complications, which indicates the primacy of the choice of P-TUEP in large and giant BPH surgery. Aims to prove the effectiveness of the use of plasma surgical methods and the scheme of complex medical postoperative prevention of late dysuric and cicatricial complications in the treatment of benign prostatic hyperplasia of large and giant sizes. Methods. The design of a retrospective cohort trial included several stages conducted at the urological center of the clinical hospital RZD-Medicine, Nizhny Novgorod in 20082019. The object of the study were patients with a confirmed diagnosis of large BPH (over 80 cm3) and giant (over 250 cm3) size, divided into the main and control groups according to the methods of surgical intervention and postoperative prevention of dysuric complications. The selection of patients was carried out by the method of paired design with an equal number of observations and maximum comparability of the initial parameters. Data analysis was carried out using the methods of parametric and nonparametric statistics, multivariate statistical analysis. Results. Comparison of the results of P-TUEP (n = 122) and open prostatectomy (n = 122) in groups of patients with large and giant BPH showed the possibility of reducing intraoperative blood loss by 1.5 times, the duration of bladder catheterization by 3.8 times, the frequency of early postoperative complications by 1.7 times and the duration of hospitalization by 2.9 times, which significantly saves hospital costs. Modification of the initial stage of P-TUEP, which consists in creating access to the prostate using new anatomical landmarks to maximize the preservation of the anterior fibrostromal complex, reduces the risk of trauma to the external urethral sphincter, which was proven by a three-fold decrease in the frequency of stress incontinence after surgery. In order to prevent late dysuric and cicatricial complications of P-TUEP, a scheme of complex medical postoperative prophylaxis with the use of a hyaluronic acid preparation was developed. It has been histologically and clinically confirmed that instillations of a hyaluronic acid solution into the bladder in combination with standard postoperative therapy make it possible to accelerate reparative processes by 24 times and get rid of irritative symptoms at 612 postoperative weeks, depending on the volume of removed BPH. Conclusion. The validity of the use, clinical and economic efficiency, high safety profile and the primacy of the choice of P-TUEP in surgery of large and giant BPH, including its modified technique and a comprehensive scheme of drug prevention of late complications, have been proven.

Restoring bladder function using motor and sensory nerve transfers: a cadaveric feasibility study.

Bladder dysfunction after nerve injury has a variable presentation, and extent of injury determines whether the bladder is spastic or atonic. The authors have proposed a series of 3 nerve transfers for functional innervation of the detrusor muscle and external urethral sphincter, along with sensory innervation to the genital dermatome. These transfers are applicable to only cases with low spinal segment injuries (sacral nerve root function is lost) and largely preserved lumbar function. Transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor contraction by thigh adduction. External urethra innervation (motor and sensory) may be accomplished by transfer of the vastus medialis nerve to the pudendal nerve. The sensory component of the pudendal nerve to the genitalia may be further enhanced by transfer of the saphenous nerve (sensory) to the pudendal nerve. The main limitations of coapting the nerve donors to their intrapelvic targets are the bifurcation or arborization points of the parent nerve. To ensure that the donor nerves had sufficient length and diameter, the authors sought to measure these parameters. Twenty-six pelvic and anterior thigh regions were dissected in 13 female cadavers. After the graft and donor sites were clearly exposed and the branches identified, the donor nerves were cut at suitable distal sites and then moved into the pelvis for tensionless anastomosis. Diameters were measured with calipers. The obturator nerve was bifurcated a mean ± SD (range) of 5.5 ± 1.7 (2.0-9.0) cm proximal to the entrance of the obturator foramen. In every cadaver, the authors were able to bring the posterior division of the obturator nerve to the vesical branch of the pelvic nerve (located internal to the ischial spine) in a tensionless manner with an excess obturator nerve length of 2.0 ± 1.2 (0.0-5.0) cm. The distance between the femoral nerve arborization and the anterior superior iliac spine was 9.3 ± 1.8 (6.5-15.0) cm, and the distance from the femoral arborization to the ischial spine was 12.9 ± 1.4 (10.0-16.0) cm. Diameters were similar between donor and recipient nerves. The chosen donor nerves were long enough and of sufficient caliber for the proposed nerve transfers and tensionless anastomosis.

Molecular Characterization of Non-Neurogenic and Neurogenic Lower Urinary Tract Dysfunction (LUTD) in SCI-Induced and Partial Bladder Outlet Obstruction Mouse Models.

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI), including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate both the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each group received an implanted bladder catheter with additional electrodes placed next to the EUS in the SCI group. UDI assessments were performed weekly for 7 weeks (pBOO group) or 8 weeks (SCI group), after which bladders were harvested for histological and transcriptome analysis. SCI mice developed detrusor sphincter dyssynergia (DSD) one week after injury with high-pressure oscillations and a significantly increased maximal bladder pressure Pmax and were unable to void spontaneously during the whole observation period. They showed an increased bladder-to-bodyweight ratio, bladder fibrosis, and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased Pmax after one week, which normalized at later time points. Increased bladder-to-bodyweight ratio and pronounced gene expression changes involving immune and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD and highlighted FGF2 as a major upregulated transcription factor during organ remodeling. We conclude that SCI-induced DSD in mice leads to profound changes in neuronal signaling and muscle contractility, leading to bladder fibrosis. In a similar time frame, significant bladder remodeling following pBOO allowed for functional compensation, preserving normal micturition parameters.

Perinatal mesenchymal stromal cells of the human decidua restore continence in rats with stress urinary incontinence induced by simulated birth trauma and regulate senescence of fibroblasts from women with stress urinary incontinence.

Stress urinary incontinence (SUI) is a condition that causes the involuntary loss of urine when making small efforts, which seriously affects daily life of people who suffer from it. Women are more affected by this form of incontinence than men, since parity is the main risk factor. Weakening of the pelvic floor tissues is the cause of SUI, although a complete understanding of the cellular and molecular mechanisms of the pathology is still lacking. Reconstructive surgery to strengthen tissue in SUI patients is often associated with complications and/or is ineffective. Mesenchymal stromal cells from the maternal side of the placenta, i.e. the decidua, are proposed here as a therapeutic alternative based on the regenerative potential of mesenchymal cells. The animal model of SUI due to vaginal distention simulating labor has been used, and decidual mesenchymal stromal cell (DMSC) transplantation was effective in preventing a drop in pressure at the leak point in treated animals. Histological analysis of the urethras from DMSC-treated animals after VD showed recovery of the muscle fiber integrity, low or no extracellular matrix (ECM) infiltration and larger elastic fibers near the external urethral sphincter, compared to control animals. Cells isolated from the suburethral connective tissue of SUI patients were characterized as myofibroblasts, based on the expression of several specific genes and proteins, and were shown to achieve premature replicative senescence. Co-culture of SUI myofibroblasts with DMSC via transwell revealed a paracrine interaction between the cells through signals that mediated DMSC migration, SUI myofibroblast proliferation, and modulation of the proinflammatory and ECM-degrading milieu that is characteristic of senescence. In conclusion, DMSC could be an alternative therapeutic option for SUI by counteracting the effects of senescence in damaged pelvic tissue.

AAV Vector Mediated Delivery of NG2 Function Neutralizing Antibody and Neurotrophin NT-3 Improves Synaptic Transmission, Locomotion, and Urinary Tract Function after Spinal Cord Contusion Injury in Adult Rats.

NG2 is a structurally unique transmembrane chondroitin sulfate proteoglycan (CSPG). Its role in damaged spinal cord is dual. NG2 is considered one of key inhibitory factors restricting axonal growth following spinal injury. Additionally, we have recently detected its novel function as a blocker of axonal conduction. Some studies, however, indicate the importance of NG2 presence in the formation of synaptic contacts. We hypothesized that the optimal treatment would be neutralization of inhibitory functions of NG2 without its physical removal. Acute intraspinal injections of anti-NG2 monoclonal antibodies reportedly prevented an acute block of axonal conduction by exogenous NG2. For prolonged delivery of NG2 function neutralizing antibody, we have developed a novel gene therapy: adeno-associated vector (AAV) construct expressing recombinant single-chain variable fragment anti-NG2 antibody (AAV-NG2Ab). We examined effects of AAV-NG2Ab alone or in combination with neurotrophin NT-3 in adult female rats with thoracic T10 contusion injuries. A battery of behavioral tests was used to evaluate locomotor function. In vivo single-cell electrophysiology was used to evaluate synaptic transmission. Lower urinary tract function was assessed during the survival period using metabolic chambers. Terminal cystometry, with acquisition of external urethral sphincter activity and bladder pressure, was used to evaluate bladder function. Both the AAV-NG2Ab and AAV-NG2Ab combined with AAV-NT3 treatment groups demonstrated significant improvements in transmission, locomotion, and bladder function compared with the control (AAV-GFP) group. These functional improvements associated with improved remyelination and plasticity of 5-HT fibers. The best results were observed in the group that received combinational AAV-NG2Ab+AAV-NT3 treatment.SIGNIFICANCE STATEMENT We recently demonstrated beneficial, but transient, effects of neutralization of the NG2 proteoglycan using monoclonal antibodies delivered intrathecally via osmotic mini-pumps after spinal cord injury. Currently, we have developed a novel gene therapy tool for prolonged and clinically relevant delivery of a recombinant single-chain variable fragment anti-NG2 antibody: AAV-rh10 serotype expressing scFv-NG2 (AAV-NG2Ab). Here, we examined effects of AAV-NG2Ab combined with transgene delivery of Neurotrophin-3 (AAV-NT3) in adult rats with thoracic contusion injuries. The AAV-NG2Ab and AAV-NG2Ab+AAV-NT3 treatment groups demonstrated significant improvements of locomotor function and lower urinary tract function. Beneficial effects of this novel gene therapy on locomotion and bladder function associated with improved transmission to motoneurons and plasticity of axons in damaged spinal cord.

Sphincter preservation techniques during radical prostatectomies: Lessons learned

Abstract Prolonged urinary incontinence represents one of the most severe complications after a radical prostatectomy procedure, significantly affecting patients’ quality of life. In an attempt to ameliorate postprostatectomy continence rates, several sphincter preservation techniques have been reported. The purpose of this article is to report several different sphincter preservation techniques and identify the ones which affect postoperative outcomes the most. For our narrative review, PubMed was searched using the keywords “sphincter,” “continence,” “preservation,” “techniques,” and “prostatectomy.” Other potentially eligible studies were identified using the reference lists of included studies. Sphincter preservation techniques can be summarized into bladder neck preservation, minimizing injury to the external urethral sphincter, and preserving the maximal length of the external sphincter and of the membranous urethra. Three anatomical structures must be recognized and protected in an attempt to maintain the sphincter complex: the bladder neck, the external urethral sphincter and the musculature of the membranous urethra. While there is strong evidence supporting the importance of bladder neck preservation, the role of maximal preservation of the external sphincter and of the intraprostatic part of the membranous urethra in improving continence rates has not yet been reported in a statistically significant manner by high-quality studies.

PP11 Presentation Time: 11:10 AM: Assessment of Brachytherapy-Induced Prostate Edema on Post-Implant Dosimetric Analysis in MRI-Assisted Radiosurgery

<h3>Purpose</h3> Prior studies have shown that brachytherapy-induced prostate edema (PE) results in altered target dose coverage on post-implant CT dosimetry in prostate cancer patients treated with low dose rate brachytherapy (LDR). The pre-plan target volume (PTV) accounts for PE by adding 1-5mm margins to the prostate for calculation of the goal dose coverage on the day of the implant (day zero, D0). However, visualization of PE on CT is limited, diminishing PE measurement accuracy. MRI-based LDR (MRI-assisted radiosurgery, MARS) improves accuracy through better delineation of target, normal structures, and seeds compared to CT. Thus, MARS may improve the accuracy of PE measurements. We investigated PE using MARS to analyze its effect on D0 dosimetry and determine if current pre-plan PTV margins are adequate in all isotopes. <h3>Materials and Methods</h3> We identified 346 patients with low to intermediate-risk prostate cancer treated with Cesium-131 (Cs-131, 15 [4.3%] patients, prescription dose (PD)=115 Gy), Iodine-125 (I-125, 83 [23.9%] patients, PD=144 Gy), or Palladium-103 (Pd-103, 248 [71.7%] patients, PD=125 Gy) MARS as definitive LDR from 2016-2021. Patients treated with hormone therapy, as a boost with external-beam RT, or for salvage were excluded. Implants were pre-planned using MRI (MIM Symphony treatment planning system) and our published nomograms verified the activity per volume within 5%. PE was measured as the change in prostate volume from the pre-plan to D0 based on physician contours. Post-implant dosimetry was performed using MRI on D0. Treatment characteristics, including pre-plan and D0 prostate volumes, prostate volumes receiving 100%, 150%, and 200% of the PD (V₁₀₀, V_150, V₂₀₀), percent of the PD going to 90% of the prostate volume (D₉₀), rectum volume receiving 100% of the PD (V₁₀₀), and external urethral sphincter (EUS) volume receiving 200% of the PD (V₂₀₀), were extracted from MIM. Simple linear regression with Pearson's correlation analysis was used to assess the effect of PE on post-implant D0 prostate V₁₀₀, V₁₅₀, V₂₀₀, and D₉₀, rectum V₁₀₀, and EUS V₂₀₀. Ordinary one-way ANOVA analysis was used to compare PE between categorical variables. <h3>Results</h3> Median age at diagnosis was 63 years. Median PSA at diagnosis was 6. 24 (6.9%) patients had GS 6 and 322 (93.1%) had GS 7. On the pre-plan, 55 (15.9%) patients had a prostate size of 0-20 ccs, 222 (64.2%) had 20-40 ccs, 63 (18.2%) had 40-60 ccs, 6 (1.7%) had 60+ ccs. On D0 analysis, the median [IQR] change in prostate volume was +28% [15-42%] as compared to the pre-plan. There was no significant difference in magnitude of PE by isotope (median change in prostate volume: +22.6% for Cs-131, +27.3% for I-125, +29.5% for Pd-103, p=0.33). There was no difference in PE by increasing number of needles (R²=0, p=0.70). PE decreased with increasing pre-plan prostate size (R²=0.05, p<0.001). Greater PE was associated with decreased post-implant D0 V₁₀₀ (<b>Graphic</b>, R²=0.08, p<0.001), V₁₅₀ (R²=0.03, p<0.001), and D₉₀(R²=0.12, p<0.001); there was no association with D0 V_{200 (}R²=0.01, p=0.06). Greater PE was associated with decreased D0 rectum V₁₀₀ (R²=0.02, p=0.02) and trended toward decreased EUS V₂₀₀ (R²=0.01, p=0.05). <h3>Conclusions</h3> MARS confirmed that patients undergoing LDR experienced PE. PE was uniform between isotopes, supporting the use of the same pre-plan PTV margins among isotopes. There was decreased D0 prostate V₁₀₀, V₁₅₀, and D₉₀ in patients with greater PE. We suggest pre-plan PTV margins as follows: 3mm laterally, 2mm anteriorly/cranially/caudally, and 0mm posteriorly. These PTV margins can help ensure adequate D0 dosimetry. <b>Graphic:</b> Correlation of post-implant D0 prostate V₁₀₀ with the magnitude of prostate edema (PE). PE was calculated as the percent change in prostate volume from the pre-plan to post-implant D0.

Neurogenic Lower Urinary Tract Dysfunction in the First Year After Spinal Cord Injury: A Descriptive Study of Urodynamic Findings.

We aimed to provide a real-world description of neurogenic lower urinary tract dysfunction within the first year after spinal cord injury with a focus on unfavorable urodynamic parameters that are associated with urological morbidity. Urodynamic investigations from 97 patients with traumatic or ischemic acute spinal cord injury and managed according to the European Association of Urology Guidelines on Neuro-Urology were analyzed at a single university spinal cord injury center at 1 month, 3 months, 6 months, and 12 months after injury. Unfavorable urodynamic parameters were defined as detrusor overactivity in combination with detrusor sphincter dyssynergia, maximum storage detrusor pressure of 40 cm H2O or higher, bladder compliance less than 20 mL/cm H2O, and vesicoureteral reflux of any grade. One or more unfavorable urodynamic parameter was observed in 87 out of 97 patients (90%) within the first year after spinal cord injury. Eighty-eight percent of the patients showed detrusor overactivity with detrusor sphincter dyssynergia, 39% a maximum storage detrusor pressure of 40 cm H2O or higher, and 7% vesicoureteral reflux. No patient developed a low-compliance bladder. Using a standardized urodynamic follow-up schedule, we found unfavorable urodynamic parameters in a majority of the population within the first year after spinal cord injury. As early treatment based on urodynamic findings might reduce the risk of deterioration of upper and lower urinary tract function, thereby improving long-term outcomes, there is need for further research regarding recommendations for a urodynamic follow-up schedule during the first year after spinal cord injury.

Continuous administration of leuprolide acetate improves urinary function in male rats with severe thoracic spinal cord injury

AimsTo determine if a continuous administration of leuprolide acetate (LA), a synthetic agonist for the gonadotrophin-releasing hormone receptor, facilitates the recovery of urinary function in spinal cord injured male rats. Main methodsMale Wistar rats were randomized into spinal cord injury (SCI; n = 7), SCI with continuous administration of LA for two weeks via implantation of a subcutaneous osmotic pump (SCI + LA; n = 7), Sham SCI (SH-SCI; n = 6) or no surgery (Intact; n = 6) groups. Micturition, hind-limb nociception and locomotor behaviors were analyzed before and after surgical procedures on days 7, 14, 21 and 28. After behavioral studies, electromyography of the external urethral sphincter (EUS-EMG) and cystometric (CMG) studies were performed in all groups. Key findingsSCI significantly decreased frequency of voids and CMG parameters (p < 0.001), abolished the bursting activity of the EUS during CMG, significantly increased hind limb sensory threshold and decreased locomotor performance in comparison to the other groups (p < 0.001). Continuous LA treatment significantly increased the frequency of voids and improved CMG parameters (p < 0.001), exhibiting bursting EUS activity during CMGs, and enhanced locomotor performance in comparison to SCI rats (p < 0.001). SignificanceSCI severely affected behavioral and functional micturition processes, including sensory and locomotor functions. Systemic and uninterrupted treatment with LA improves the recovery of micturition behavior and the synergistic function of the EUS. Furthermore, sensory and locomotor responses were also improved in SCI rats. This procedure may have a therapeutic potential to facilitate urinary function recovery in patients with SCI.

Exosome biopotentiated hydrogel restores damaged skeletal muscle in a porcine model of stress urinary incontinence

Urinary incontinence afflicts up to 40% of adult women in the United States. Stress urinary incontinence (SUI) accounts for approximately one-third of these cases, precipitating ~200,000 surgical procedures annually. Continence is maintained through the interplay of sub-urethral support and urethral sphincter coaptation, particularly during activities that increase intra-abdominal pressure. Currently, surgical correction of SUI focuses on the re-establishment of sub-urethral support. However, mesh-based repairs are associated with foreign body reactions and poor localized tissue healing, which leads to mesh exposure, prompting the pursuit of technologies that restore external urethral sphincter function and limit surgical risk. The present work utilizes a human platelet-derived CD41a and CD9 expressing extracellular vesicle product (PEP) enriched for NF-κB and PD-L1 and derived to ensure the preservation of lipid bilayer for enhanced stability and compatibility with hydrogel-based sustained delivery approaches. In vitro, the application of PEP to skeletal muscle satellite cells in vitro drove proliferation and differentiation in an NF-κB-dependent fashion, with full inhibition of impact on exposure to resveratrol. PEP biopotentiation of collagen-1 and fibrin glue hydrogel achieved sustained exosome release at 37 °C, creating an ultrastructural “bead on a string” pattern on scanning electron microscopy. Initial testing in a rodent model of latissimus dorsi injury documented activation of skeletal muscle proliferation of healing. In a porcine model of stress urinary incontinence, delivery of PEP-biopotentiated collagen-1 induced functional restoration of the external urethral sphincter. The histological evaluation found that sustained PEP release was associated with new skeletal muscle formation and polarization of local macrophages towards the regenerative M2 phenotype. The results provided herein serve as the first description of PEP-based biopotentiation of hydrogels implemented to restore skeletal muscle function and may serve as a promising approach for the nonsurgical management of SUI.

A time-course study of urodynamic analyses in rat models with dopaminergic depletion induced through unilateral and bilateral 6-hydroxydopamine injections

Bladder dysfunction is a common non-motor disorder in Parkinson's disease (PD). This study attempted to determine the bladder dysfunction with disease progression in the PD rat model produced from unilateral/bilateral injections of 6-hydroxydopamine (6-OHDA). Cystometrographic (CMG) and external urethral sphincter electromyographic (EUS-EMG) measurements were scheduled in a time-course manner to determine the disease timing, onset, and severity. Animals were allotted into normal control, unilateral, bilateral 6-OHDA injected groups and subjected to scheduled CMG, EUS-EMG analyses at weeks 1, 2, and 4. The urodynamic results concluded that voiding efficiency (VE) was reduced in both unilateral and bilateral PD rats at all-time points. VE had decreased from 57±11% to 31±7% in unilateral PD rats and in bilateral PD rats, a decreased VE of 20±6% was observed compared to control and unilateral PD rats. The EMG results in unilateral PD rats indicated declines in bursting period (BP) (3.78-2.94s), active period (AP) (93.38-88.75ms), and silent period (SP) (161.62-114.30ms). A sudden reduction was noticed in BP (3.62-2.82s), AP (92.21-86.01ms), and SP (128.61-60.16ms) of bilateral PD rats than in control and unilateral PD rats. Histological evidence exhibited a progressive dopaminergic neurons (DA) depletion in the substantia nigra (SN) region in 6-OHDA lesioned rats. The experimental outcomes strongly implied that significant variations in bladder function and VE decline were due to the depletion of DA neurons in the SN region of the brain.

Botulinum toxin A injection to the external urethral sphincter for voiding dysfunction in females: A tertiary center experience.

The aim of this study is to examine the functional outcomes of ona-botulinum toxin A (BTX-A) injection into the external urethral sphincter (EUS) for female patients with nonneurogenic nonrelaxing sphincter as the underlying cause of voiding dysfunction (VD). A retrospective analysis was performed for all the patients with the urodynamic findings of higher than expected maximum urethral closure pressure (MUCP) who received their first injection during the study period. All patients were evaluated with preoperative videourodynamic study and urethral pressure profilometry and received 100 U of EUS BTX-A. Patients aged less than 18 years and those with neurogenic bladder were excluded. All patients were followed up with the free flow, postvoid residuals (PVR), and patient global impression of improvement (PGI-I) scale at 6 weeks and then at 3 monthly intervals. We identified 35 female patients with a mean age of 37.5 ± 15 years (range 18-72 years) with a mean follow-up of 20 months. More than 50% of patients had a history of prior surgical intervention and 28 (80%) patients were catheter dependent, a suprapubic catheterization, or clean intermittent self-catheterization. Mean MUCP was 97.1 ± 22 cm of water. After treatment with BTX-A, 21 (60%) patients were able to void per urethral (p = 0.02). The mean maximum flow rate (Qmax) improved from 8.8 to 11 mls/s and the mean PVRdecreased from 200 to 149 mls (p &lt; 0.05). On multivariate analysis, we identified high preoperative PVR, high preoperative actualMUCP, and previous surgical intervention (urethral dilatation, sacral neuromodulation, and pelvic surgery) as predictors of successful voiding restoration. The mean duration of response was 4.7 months, 46% of patients requested repeat injection, and 29% were established on maintenance injections. On the 5-point PGI-I score, 13 (37%), 12 (34%), and 10 (29%) patients reported good, some, and no improvement, respectively. Quality of life was also improved in 60% of patients. Two patients had transient stress urinary incontinence (for&lt;6 weeks) and there were no significant long-lasting adverse events. EUS BTX-A is a valid treatment option for VD considering therapeutic options are limited. The patient must be made aware of the need for repeat treatments.