An innovative electrical neurostimulation approach to mimic reflexive urination control in spinal cord injury models.

Neurogenic lower urinary tract dysfunction (NLUTD) is a frequent consequence of spinal cord injury (SCI), leading to symptoms that significantly impact quality of life. Although many life-saving techniques are available, current treatment strategies for managing NLUTD still exhibit limitations and drawbacks. Here, we introduce a new electrical neuromodulation strategy involving electrical stimulation of the major pelvic ganglion (MPG) to initiate bladder contraction, in conjunction with innovative programmable (IPG) electrical stimulation on the pudendal nerve (PN) to induce external urethral sphincter (EUS) relaxation in freely moving or anesthetized SCI mice. Furthermore, we conducted the void spot assay, and cystometry coupled with EUS electromyography (EMG) recordings to evaluate voiding function, and monitor bladder pressure and EUS activity. Our findings demonstrate that our novel electrical neuromodulation approach effectively triggers coordinated bladder muscle contraction and EUS relaxation, effectively counteracting SCI-induced NLUTD. Additionally, this electrical neuromodulation method enhances voiding efficiency, closely resembling natural reflexive urination in SCI mice. Thus, our study offers a promising electrical neurostimulation approach aimed at restoring physiological coordination and potentially offering personalized treatment for improving voiding efficiency in individuals with SCI-associated NLUTD.

Predictive Factors for the Successful Outcome of Urethral Sphincter Injections of Botulinum Toxin A for Non-Neurogenic Dysfunctional Voiding in Women.

PURPOSE: Dysfunctional voiding (DV) is not uncommon in women with non-neurogenic voiding dysfunction. Because of its unknown pathophysiology, effective and durable treatment is lacking. This study aimed to analyze the results of treatment and predictive factors for a successful outcome of botulinum toxin A (BoNT-A) treatment in female patients with DV. METHODS: In total, 66 women with DV confirmed by a videourodynamic study (VUDS) were treated with a BoNT-A injection into the urethral sphincter once (n = 33) or several times (n = 33). VUDS was performed before (baseline) and after the BoNT-A treatment. Patients with a global response assessment of the voiding condition of 2 or 3 and a voiding efficiency (VE) of >20% than baseline were considered to have a successful outcome. The baseline demographics, VUDS parameters, and VUDS DV subtypes were compared between the successful and failed groups. Predictive factors for a successful outcome were investigated by logistic regression analyses. RESULTS: Successful and failed outcomes were achieved in 27 (40.9%) and 39 (59.1%) women, respectively. After BoNT-A injections, the maximum flow rate (Qmax), voided volume, and VE all significantly increased, and the postvoid residual (PVR) was slightly improved. No significant difference in the number of injections and medical comorbidity was found between the groups. However, the successful group had a higher incidence of previous pelvic surgery. No significant difference in the treatment outcome was found among patients with different urethral obstruction sites. Significant improvements in Qmax, voided volume, PVR, VE, and the bladder outlet obstruction (BOO) index were noted in the successful group. A lower VE at baseline and a history of surgery were identified as predictive factors for a successful outcome of BoNT-A injections for treating DV. CONCLUSION: BoNT-A injections into the urethral sphincter can effectively improve VE in 40.9% of women with DV. Women with higher BOO grades and previous pelvic surgery are predicted to have a successful treatment outcome.

What maximal urethral closure pressure threshold predicts failure of mid-urethral sling surgery?

OBJECTIVE: Low Maximal Urethral Closure Pressure (MUCP) is linked to unfavourable outcome of anti-incontinence surgery, however the cut-off value varied within studies. This study aimed to predict the cut-off value of MUCP that contributes to poor outcome of Mid-Urethral Sling (MUS) surgery in Urinary Stress Incontinence (USI) patients. MATERIALS AND METHODS: Records of 729 women underwent MUS procedure from January 2004 to April 2017 reviewed. Patients were divided into four MUCP groups, which were <20 cmH2O (≥20 and < 40) cmH2O (≥40 and ≤ 60) cmH2O and >60 cmH2O. Objective evaluation comprising 72-h voiding diary, multichannel urodynamic study (UDS) and post-operative bladder neck angle measurement. Subjective evaluation through validated urinary symptoms questionnaires. Primary outcome was objective cure rate of negative urine leak on provocative filling cystometry and 1-h pad test weight <2 g, and subjective cure rate was negative response to question 3 of UDI-6. Secondary outcome was identifying risk factors of cure failure for MUS in low MUCP groups. To identify the risk factors of cure failure, MUCP groups were narrowed down into <40 cmH2O or ≥40 cmH2O. RESULTS: Total of 688 women evaluated. Overall objective cure rate was 88.2% with subjective cure rate of 85.9%. Objective and subjective cure rates were lower in groups with low MUCP <40 cmH2O. Failure of MUS correlate significantly in patients with low MUCP <40 cmH20, bladder neck angle <30° and Functional urethral length (FUL) < 2 cm. CONCLUSION: Women with MUCP <40cmH2O, bladder neck angle <30° and FUL < 2 cm are more likely to have unfavorable outcome following MUS surgery. We proposed the cut-off low MUCP <40cmH2O as predictor for fail MUS surgery in SUI patients.

Do peri-operative changes in voiding function and pelvic organ mobility predict improvement in urgency urinary incontinence following prolapse surgery?

OBJECTIVES: To evaluate whether peri-operative changes in voiding function, pelvic organ descent and urethral mobility predict improvement in urgency urinary incontinence (UUI) following prolapse surgery. METHODS: A retrospective study of women undergoing prolapse surgery without a history of or without a concomitant anti-incontinence surgery at a tertiary unit between 2005 and 2019. All patients underwent a pre- and post-operative standardised interview, POP-Q examination, uroflowmetry and 4D translabial ultrasound. Post processing of ultrasound volume data was performed to assess pelvic organ descent and functional urethral anatomy. RESULTS: The datasets of 123 women were analysed. Mean follow-up was 5.5 months (SD 3.2). Mean age was 61 years (SD 11.7). UUI was reported by 68 before and 44 after operation (p = 0.001 for the reduction). Among those with pre-operative UUI, 34 reported cure of UUI, 20 improvement, 9 no change and 5 worsened UUI after their operation. De novo UUI was reported in 11. Fifty-seven women reported voiding dysfunction before and 32 after operation (p = 0.09 for the reduction). Abnormal uroflowmetry was noted in 63 women before and 37 after operation (p = 0.003 for change). On binary logistic regression, improved/cured UUI was associated with improved subjective voiding function (p = 0.003) and reduced residual urine volume (p = 0.02), but not with peri-operative changes in pelvic organ descent or functional urethral anatomy. CONCLUSION: Prolapse surgery resulted in short- to medium- term improvement in UUI. This was associated with subjective improvement in voiding function and with a reduction in post-void residual urine volume. SUMMARY: Prolapse surgery was associated with improvement in UUI which in turn was associated with subjectively improved voiding and reduced residual urine volume.

In silico assessment of the reliability and performance of artificial sphincter for urinary incontinence.

BACKGROUND: The standard artificial urinary sphincter (AUS) is an implantable device for the treatment of urinary incontinence by applying a pressure loading around the urethra through an inflatable cuff, often inducing no-physiological stimulation up to tissue degenerative phenomena. A novel in silico approach is proposed to fill the gap of the traditional procedures by providing tools to quantitatively assess AUS reliability and performance based on AUS-urethra interaction. METHODS: The approach requires the development of 3D numerical models of AUS and urethra, and experimental investigations to define their mechanical behaviors. Computational analyses are performed to simulate the urethral lumen occlusion by AUS inflation under different pressures, and the lumen opening by applying an intraluminal pressure progressively increased under the AUS action (Abaqus Explicit solver). The AUS reliability is evaluated in terms of tissue stimulation by the mechanical fields potentially responsible for vasoconstriction and tissue damage, while the performance by the intraluminal pressure that causes the lumen opening for a specific occlusive pressure, showing the maximum urethral pressure for which continence is guaranteed. RESULTS: The present study implemented the procedure considering the gold standard AMS 800 and a novel patented AUS. Results provided the comparison between two sphincteric devices and the evaluation of the influence of different building materials and geometrical features on the AUS functionality. CONCLUSIONS: The approach was developed for the AUS, but it could be adapted also to artificial sphincters for the treatment of other anatomical dysfunctions, widening the analyzable device configurations and reducing experimental and ethical efforts.

Treatment algorithm for the comprehensive management of severe lichen sclerosus in boys based on the pathophysiology of the disease.

INTRODUCTION: It is estimated that approximately one out of 200 boys has the diagnosis of lichen sclerosus (LS), previously referred to as BXO (balanitis xerotica obliterans). Severe progressive disease is rare however, mismanagement of urethral tissues may contribute to progression of LS. STUDY DESIGN: The current literature regarding the management of severe lichen sclerosus was reviewed alongside our management of seven patients with ages ranging from six to ten years of age with severe lichen sclerosus who required surgical intervention. These patients were identified out of a busy pediatric practice that saw 5507 patients during the four-year span. Based on the pathophysiology of lichen sclerosus, urethral anatomy, and our management an algorithm was developed for medical and surgical management. RESULTS: All patients received initial medical treatment with topical steroids. Three patients underwent urethral mobilization and serial biopsy. One of these patients with severe disease required a second distal urethral mobilization. Three patients were treated with circumcision, and one is responding well to topical steroids after complex reconstruction. None developed postoperative urethral disease. DISCUSSION: Lichen sclerosus affects squamous epithelium but can extend to unaffected tissue if traumatized via the Koebner phenomenon. There are no randomized control trials for the management of the disease. Thus, appropriate early management with avoidance of urethral dilation or incision may prevent extension down the urethra that can lead to severe stricture disease. Several authors identified this as one of the worst forms of stricture diseases to manage. Based on the pathophysiology of the disease and our 4-year experience treating patients, we propose an algorithm for management of severe lichen sclerosus in boys. The diagnosis of lichen sclerosus in boys requires a high level of suspicion, and early biopsies should be obtained if suspected. If identified before circumcision or meatotomy, initial treatment should be medical. If the patient fails topical steroid therapy, circumcision and biopsy are the initial recommended surgical approach. Optimally, a biopsy with the first meatotomy establishes the diagnosis. If the disease persists, urethral mobilization may represent a curative treatment as it advances healthy urethra and allows complete removal of distal squamous epithelium instead of traumatic repeated dilations or incisions. CONCLUSION: This paper summarizes the available literature on the management of severe LS and provides a flow diagram based on the pathophysiology of the disease and our experience sever cases.

Constrictive versus compressive bladder outflow obstruction in men: Does it matter?

INTRODUCTION: Bladder outflow obstruction (BOO) is a urethral resistance (UR) at a level above a clinically relevant threshold. UR is currently graded in terms of the existence and severity of the BOO based on maximum flowrate and associated detrusor pressure only. However, the pressure-flow relation throughout the course of voiding includes additional information that may be relevant to identify the type of BOO. This study introduces a new method for the distinction between the provisionally called compressive and constrictive types of BOO and relates this classification to underlying patient and urodynamic differences between those BOO types. METHODS: In total, 593 high-quality urodynamic pressure-flow studies in men were included in this study. Constrictive BOO was identified if the difference Δp between the actual minimal urethral opening pressure (pmuo) and the expected pmuo according to the linearized passive urethral resistance relation (linPURR) nomogram was >25 cmH2O. Compressive BOO is identified in the complementary case where the pressure difference Δp ≤ 25 cmH2O. Differences in urodynamic parameters, patient age, and prostate size were explored. RESULTS: In 81 (13.7%) of the cases, constrictive BOO was found. In these patients, the prostate size was significantly smaller when compared to patients diagnosed with compressive BOO, while displaying a significantly lower maximum flowrate, higher detrusor pressure at maximal flowrate and more postvoid residual (PVR). CONCLUSION: This study is an initial step in the validation of additional subtyping of BOO. We found significant differences in prostate size, severity of BOO, and PVR, between patients with compressive and constrictive BOO. Subtyping of voiding-outflow dynamics may lead to more individualized management in patients with BOO.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model.

Several neurologic diseases including spinal cord injury, Parkinson's disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

The clinical study of urinary flow parameters after drag-and-bond anastomosis for ileal orthotopic neobladder reconstruction.

AIM: To assess the viability of this procedure in laparoscopic radical cystectomy with ileal orthotopic neobladder reconstruction, the objective of this study is to examine the relationship between urinary flow parameters of urethral drag-and-bond anastomosis in the reconstruction of the ileal orthotopic neobladder. METHODS: 36 patients with bladder cancer underwent laparoscopic radical cystectomy with ileal orthotopic neobladder reconstruction at Jiangxi provincial people's hospital between June 2016 and January 2021,16 patients underwent intermittent urethral anastomosis, while 20 patients underwent neobladder-urethral drag-and-bond anastomosis. The maximum bladder capacity, residual urine output, maximum urinary flow rate, and outlet morphology of the new bladder neck were all monitored throughout postoperative follow-up regularly. RESULTS: There was no significant difference between the urethral drag-and-bond anastomosis group (group A) and the conventional anastomosis group (group B) at 3 months and 12 months after surgery, and the maximum bladder capacity (3 months, 488.35 ± 51.56 ml vs 481.06 ± 40.61 ml, t = -0.462, P = 0.647; 12 months, 496.35 ± 51.09 ml vs 476.56 ± 56.33 ml, t = -1.103, P = 0.278), residual urine output (3 months, 44.15 ± 24.12 ml vs 38.69 ± 21.82 ml, t = -0.704, P = 0.486;12 months, 49.65 ± 26.95 ml vs 36.75 ± 21.96 ml, t = -1.546, P = 0.131) and maximum urine flow rate (3 months, 12.36 ± 2.63 ml/s vs 13.60 ± 2.82 ml/s, t = 1.361, P = 0.182;12 months, 12.18 ± 3.14 ml/s vs 11.13 ± 3.01 ml/s, t = -1.004, P = 0.322) of the two groups were not significant (P > 0.05). The new bladder outlet morphology was not distorted in group A patients, the continuity was good, and there were fewer associated complications. CONCLUSIONS: There was no significant difference in postoperative urodynamic parameters between the urethral drag-and-bond anastomosis group and the conventional anastomosis group, and the postoperative new bladder outlet was in good shape, with clinical significance.

Perineal ultrasound to assess the urethral spatial movement in stress urinary incontinence in women.

BACKGROUND: Perineal ultrasound as a non-invasive method for the diagnosis of female stress urinary incontinence has attracted more and more attention. However, the criteria for stress urinary incontinence in women using perineal ultrasound have not been fully established. Our study aimed to evaluate characteristics of the urethral spatial movement with perineal ultrasonography. METHODS: A total of 136 female patients with stress urinary incontinence and 44 controls were enrolled. Stress urinary incontinence was diagnosed using the International Consultation on Incontinence Questionnaire Short Form, medical history and physical examination, and severity was assessed using a 1 h pad test. We described the mobility of four equidistant points (A-D) located along the urethra length. The retrovesical and urethral rotation angles were measured using perineal ultrasonography at rest and during the maximal Valsalva maneuver. RESULTS: Patients with stress urinary incontinence showed a more significant vertical movement at Points A, B and C than controls. The mean variations in the retrovesical angle were significantly larger in patients with stress urinary incontinence at rest and during the Valsalva maneuver than in controls (21.0 ± 16.5° vs. 14.7 ± 20.1°, respectively). The cut-off value for the retrovesical angle variation was 10.7° with 72% sensitivity and 54% specificity. There was a receiver-operating characteristic curve area of 0.73 and 0.72 for Points A and B, respectively. A cut-off of 10.8 mm, and 9.4 mm provided 71% sensitivity and 68% specificity and 67% sensitivity and 75% specificity, respectively. CONCLUSIONS: The spatial movement of the bladder neck and proximal urethra, and variations in the retrovesical angle may be correlated with clinical symptoms and facilitate to the assessment of SUI.

The potential involvement of MRP5 pump in urethral dysfunction in streptozotocin-induced diabetic rats.

PURPOSE: To examine the effects of i.v. administration of MK-571, a MRP4/5 pump inhibitor, on urethral function in the urethane-anesthetized rat, and the changes of urethral multidrug resistance protein 5 (MRP5) pump in streptozotocin (STZ)-induced diabetes mellitus (DM) rats. METHODS: Isovolumetric cystometry and urethral perfusion pressure (UPP) measurements were carried out in normal control (NC) group and 8week DM groups under urethane anesthesia. When stable rhythmic bladder contractions were showed, UPP parameters were recorded after successive administration of various dose of MK-571. Additionally, urethral cyclic guanosine monophosphate (cGMP) protein level was evaluated by ELISA, and changes of MRP5 pump and neurogenic nitric oxide synthase (nNOs) in the urethra were examined with immunohistochemical staining and Western blot analysis. RESULTS: In NC group, UPPnadir was significantly decreased but UPP change increased after administration of MK-571, while no significant differences in UPP parameters were observed in 8-week DM group. Furthermore, urethral MRP5 protein level was up-regulated, whereas urethral cGMP and nNOS protein levels were down-regulated in 8-week DM group. CONCLUSIONS: MK-571 could not restore NO-mediated urethral relaxation dysfunction in DM rats, which may be attributed to the up-regulation of urethral MRP5 pump, and thus decrease of intracellular cGMP concentration in the urethra. These novel results would be useful for a better understanding of DM-related lower urinary tract dysfunction LUT (LUTD). Also, they could be helpful to study the importance of MRP pumps in the control of urethral relaxation mechanisms under physiological and pathological states.

THE RELIABILITY OF URODYNAMIC ASSESSMENT IN CONFIRMATION OF STRESS URINARY INCONTINENCE IN RELATION TO BONNEY TEST.

According to the International Continence Society, stress (static) urinary incontinence is defined as any involuntary loss of urine on effort or physical exertion, due to which intravesical pressure overcomes urethral pressure, with no detrusor activity. Urodynamic testing accurately assesses the function of the bladder and urethra. The urodynamic assessment includes three tests: cystometry, uroflowmetry and profilometry (determination of urethral pressure profile). Prior to urodynamic assessment, it is mandatory to rule out urinary tract infection since it is an invasive test. Urethral profilometry is a technique that measures pressure in the urethra and bladder at rest, during stressful actions, and during the act of miction. Its main purpose is to evaluate the sphincter mechanism. During the examination, a special catheter is used, which is being slowly pulled out from the bladder neck throughout the urethra, with continuous recording of intraurethral pressure. In addition to measuring urethral pressures, stress urinary incontinence is also very successfully proven by the cough test and Bonney test. If, on forced cough, the urine escapes uncontrollably, and continence is restored by finger lifting the neck of the bladder, the diagnosis of static incontinence is confirmed. At our urogynecologic clinic, urodynamic examination is being routinely performed. In the present study, we included patients previously treated for urinary stress incontinence and compared their results of urodynamic assessment to the results of Bonney test. Of the 43 subjects in whom stress incontinence was proven with Bonney test, we recorded an appropriate profilometry result in 13 cases.

Improvement of urethral dysfunction by 5-HT1A receptor agonist NLX-112 in diabetic rats.

OBJECTIVE: To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 32) were divided into two groups: rats with type 1 diabetes mellitus (T1DM) and age-matched normal control rats (NC). T1DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Isovolumetric cystometry and urethral perfusion pressure (UPP) were evaluated 10 weeks postinjection in rats (n = 9 per group). The selective 5-HT1A receptor antagonist, WAY-100635 maleate salt, was administered after NLX-112 hydrochloride dose-response curve was generated (intravenously). The remaining rats were used for immunofluorescence and Western blot assays. RESULTS: Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In T1D rats, NLX-112 hydrochloride (0.003-1.0 mg/kg) induced dose-dependent decreases in UPP nadir, IP max, high-frequency oscillations (HFOs) rate; and increases in UPP change and HFOs amplitude. WAY-100635 maleate salt (0.3 mg/kg) partially or completely reversed the NLX-112-induced changes. Immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord dorsolateral nucleus, but the expression was significantly higher in the T1D rats. Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats. CONCLUSIONS: Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT1A receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction.

Numerical investigation of urethra flow characteristics in benign prostatic hyperplasia.

BACKGROUND AND OBJECTIVE: Conventional practice includes a limited depiction of urethral pressure and flows based on fragmented gross clinical observations. However, with technological advancements in simulations, computational fluid dynamics (CFD) can provide an alternative approach to predict the bladder pressure with a concordant quantitative flow field in the urethra. Thus, this study aims to comprehensively analyze the urine flow characteristics in various urethra models using simulations. METHODS: Three-dimensional urethra models were constructed for seven specific subjects based on clinical radiographs. Simulations with Reynolds averaged Navier-Stokes model were performed to quantitatively investigate the urine flow under various volume flow rate of voided urine. RESULTS: Under benign prostatic hyperplasia, the spindle shape of the prostatic urethra (PRU) generates wake flow. The wake flow was also observed in several regions downstream of the PRU, depending on the urethra shape. This wake flow resulted in total pressure loss and urinary tract dysfunction. When comparing pre- and post-operative urethra models, the bladder pressure decreased by 14.98% in P04 and 4.67% in P06. Thus, we identified variability between surgical results of patients. The bladder pressure according to the volume flow rate of voided urine was investigated using simulations and the theoretical consideration based on hydrodynamics. In theoretical consideration, the bladder pressure was expressed as a second-order polynomial for volume flow rate. These results concur with the simulation results. CONCLUSION: Numerical simulation can describe the urine flow field in the urethra, providing the possibility to predict the bladder pressure without requiring painful, invasive interventions, such as cystoscopy. Furthermore, effective treatments to improve urination function can be formulated to be patient-specific, by detecting causes and problem regions based on quantitative analysis and predicting post-surgical outcomes.

Pressure transmission theory-The Rasputin of incontinence.

BACKGROUND: Enhorning's pressure transmission theory (PTT), though mortally wounded by multiple invalidations from the 1990 Integral Theory of female urinary incontinence (IT), like Rasputin, continues to survive as a theory for continence and incontinence. AIM: To examine the questions: How has the PTT survived? What is its contribution to knowledge? METHODS: Eleven different invalidations are presented based on images, pressure readings, clinical examples, experiments by the author, and others, for example, flow mechanics, finite element models, and surgical operations. RESULTS: Each of the 11 invalidations prima facie invalidate the PTTs of enhorning and others. CONCLUSIONS: "How has the PTT survived?" Having provided a plausible explanation for all abdominal stress urinary incontinence operations since 100 years, PTT, unsurprisingly, like climate change today, had become an entrenched convention which abdicated the need for midurethral sling (MUS) surgeons to learn the very different functional surgical anatomy underlying the MUS. "Has the PTT progressed knowledge, or retarded it?" This lack of knowledge by the surgeons of how and why the MUS works could be held responsible for the large number of major complications reported by the TVT: including, transected urethras, obturator nerve damage, perforation of external iliac vessels, more than 20 deaths. The role of the sling is to strengthen the pubourethral neoligament to prevent the urethra opening out under stress, not to elevate it. Elevating the sling remains the major cause of the most frequent complication of the MUS today, postoperative urinary retention.

Large Animal Models for Investigating Cell Therapies of Stress Urinary Incontinence.

Stress urinary incontinence (SUI) is a significant health concern for patients affected, impacting their quality of life severely. To investigate mechanisms contributing to SUI different animal models were developed. Incontinence was induced under defined conditions to explore the pathomechanisms involved, spontaneous recovery, or efficacy of therapies over time. The animal models were coined to mimic known SUI risk factors such as childbirth or surgical injury. However, animal models neither reflect the human situation completely nor the multiple mechanisms that ultimately contribute to the pathogenesis of SUI. In the past, most SUI animal studies took advantage of rodents or rabbits. Recent models present for instance transgenic rats developing severe obesity, to investigate metabolic interrelations between the disorder and incontinence. Using recombinant gene technologies, such as transgenic, gene knock-out or CRISPR-Cas animals may narrow the gap between the model and the clinical situation of patients. However, to investigate surgical regimens or cell therapies to improve or even cure SUI, large animal models such as pig, goat, dog and others provide several advantages. Among them, standard surgical instruments can be employed for minimally invasive transurethral diagnoses and therapies. We, therefore, focus in this review on large animal models of SUI.

Therapeutic Efficacy of Urethral Sphincteric Botulinum Toxin Injections for Female Sphincter Dysfunctions and a Search for Predictive Factors.

External urethral sphincter (EUS) dysfunction is a common, bothersome female voiding dysfunction. This study aims to analyze the characteristics of different types of female EUS dysfunction, as well as to determine the outcome predictors of sphincteric botulinum toxin A (BoNT-A) injection. Women receiving sphincteric BoNT-A injections for refractory EUS dysfunction were retrospectively reviewed. A comparison of the baseline clinical, urodynamic parameters and the treatment responses were made for patients with different EUS dysfunctions. A total of 106 females were included. Significantly increased detrusor overactivity, detrusor contracting pressure and the bladder outlet obstruction index with decreased urge sensation were noted in patients diagnosed with dysfunctional voiding or detrusor sphincter dyssynergia comparing to those diagnosed with poor relaxation of the external urethral sphincter. The average subjective improvement rate was 67% for the injection. The therapeutic effect was not affected by the type of EUS dysfunction. The multivariate analysis revealed that bladder neck narrowing and catheterization history were predictive of negative outcomes. There is a distinct urodynamic presentation for each type of female EUS dysfunction. Sphincteric BoNT-A injection provides a good therapeutic outcome for refractory EUS dysfunction. A narrowing bladder neck and a history of catheterization suggest poor therapeutic outcomes.

Therapeutic efficacy of biofeedback pelvic floor muscle exercise in women with dysfunctional voiding.

Dysfunctional voiding (DV), a voiding dysfunction due to hyperactivity of the external urethral sphincter or pelvic floor muscles leading involuntary intermittent contractions during voiding, is not uncommon in neurologically normal women with lower urinary tract symptoms (LUTS). We aimed to investigate the therapeutic efficacy of biofeedback pelvic floor muscle training (PFMT) in female patients with DV and to identify the therapeutic efficacy. Thirty-one patients diagnosed with DV. All participates completed the 3-month biofeedback PFMT program, which was conducted by one experienced physiotherapist. At 3 months after treatment, the assessment of treatment outcomes included global response assessment (GRA), and the changes of clinical symptoms, quality of life index, and uroflowmetry parameters. 25 (80.6%) patients had successful outcomes (GRA ≥ 2), and clinical symptoms and quality of life index significantly improved after PFMT. Additionally, uroflowmetry parameters including maximum flow rate, voided volume, voiding efficiency, total bladder capacity, voiding time, and time to maximum flow rate significantly improved after PFMT treatment. Patients with the history of recurrent urinary tract infection in recent 1 year were found to have unsatisfied therapeutic outcomes. In conclusion, biofeedback PFMT is effective in female patients with DV with significant improvements in clinical symptoms, quality of life, and uroflowmetry parameters. The history of urinary tract infection in recent 1 year is a negative predictor of successful outcome.

Exon skip-inducing variants in FLNA in an attenuated form of frontometaphyseal dysplasia.

Pathogenic variation in the X-linked gene FLNA causes a wide range of human developmental phenotypes. Loss-of-function is usually male embryonic-lethal, and most commonly results in a neuronal migration disorder in affected females. Gain-of-function variants cause a spectrum of skeletal dysplasias that present with variable additional, often distinctive, soft-tissue anomalies in males and females. Here we present two, unrelated, male individuals with novel, intronic variants in FLNA that are predicted to be pathogenic. Their phenotypes are reminiscent of the gain-of-function spectrum without the skeletal manifestations. Most strikingly, they manifest urethral anomalies, cardiac malformations, and keloid scarring, all commonly encountered features of frontometaphyseal dysplasia. Both variants prevent inclusion of exon 40 into the FLNA transcript, predicting the in-frame deletion of 42 amino acids, however the abundance of FLNA protein was equivalent to that observed in healthy individuals. Loss of these 42 amino acids removes sites that mediate key FLNA functions, including binding of some ligands and phosphorylation. This phenotype further expands the spectrum of the FLNA filaminopathies.