Increase In Urethral Pressure Research Articles

Burst Stimulation Evokes Increased Bladder and Urethral Pressure in Patients With Sacral Neuromodulation, Indicating Potential Activation of the Autonomic Nervous System: A Pilot Study

ObjectivesCurrently, sacral neuromodulation (SNM) outcomes are often suboptimal, and changing stimulation parameters might improve SNM efficacy. Burst stimulation mimics physiological burst firing of the nervous system and might therefore benefit patients treated with SNM. The purpose of the present pilot study was to evaluate the effect of various Burst SNM paradigms on bladder and urethral pressure in patients with overactive bladder (OAB) or nonobstructive urinary retention (NOUR). Materials and MethodsThe bladder was filled to 50% of its capacity under general anesthesia in six patients with an implanted sacral lead for SNM purposes. Bladder pressure, and mid- and proximal urethral pressure were measured using conventional (Con-) SNM and various Burst SNM paradigms (10-20-40 Hz interburst frequency) with increasing amplitudes up to 5 mA for Con-SNM and 4 mA for Burst SNM. ResultsBurst SNM caused a substantial increase in both bladder and urethral pressure. In contrast, Con-SNM caused a milder increase in urethral pressure, and only one patient showed a modest increase in bladder pressure. Furthermore, the pressure increase was higher in the proximal urethra than in the midurethra using Burst-SNM, whereas Con-SNM caused comparable increases in proximal and midurethra pressure. ConclusionsBurst SNM induces bladder contraction compared with Con-SNM and induces higher pressure increases in bladder and proximal urethra than does Con-SNM in patients with OAB or NOUR, indicating a higher degree of autonomic nervous system stimulation. The observed responses could not be fully explained by the total charge of the Burst SNM paradigms, which suggests the importance of individual Burst SNM parameters, such as frequency and amplitude. Future studies should assess the feasibility and efficacy of Burst SNM in awake patients.

The female urethral closure mechanism during physical stress.

The closure of the urethra under the condition of stress is the result of a reflex contraction of the urethral rhabdosphincter and pelvic floor muscles. This is likely induced by activity of the abdominal muscles due to a sudden increase in abdominal pressure. This reflex contraction with an increase of urethral pressure occurs a few milliseconds before an increase in intraabdominal pressure. The urethral pressure increase during stress is only possible with fixation of the urethra by the pubourethral ligaments (PUL), facilitating urethral kinking. The highest and most important increase in pressure and resistance occurs in the distal urethra due to this kinking of the urethra.

Pudendal Nerve Block by Adaptively Stepwise Increasing the Intensity of High-Frequency (10 kHz) Biphasic Stimulation

ObjectiveThe purpose of this study is to determine whether adaptively stepwise increasing the intensity of a high-frequency (10 kHz) biphasic stimulation (HFBS) can produce nerve conduction block without generating a large initial response. Materials and MethodsIn anesthetized cats, three cuff electrodes were implanted on the left pudendal nerve for stimulation or block. The urethral pressure increase induced by pudendal nerve stimulation was used to measure the pudendal nerve block induced by HFBS. ResultsHFBS applied suddenly with a large step increase in intensity induced a large (86 ± 16 cmH2O) urethral pressure increase before it blocked pudendal nerve conduction. However, HFBS applied by adaptively stepwise increasing the intensity every 10 to 60 seconds over a long period (33–301 minutes; average 108 ± 35 minutes) with many small intensity increases (0.005–0.1 mA) induced no response or low-amplitude high-frequency urethral pressure changes before it blocked pudendal nerve conduction. The minimal HFBS intensities required by the two different methods to block pudendal nerve conduction are similar. ConclusionThis study is important for better understanding the possible mechanisms underlying the HFBS-induced nerve block and provides the possibility of developing a new nerve block method for clinical applications in which an initial large response is a concern.

Characterization of bilateral, pudendal nerve-evoked, urethral rhabdosphincter contractions in anesthetized cats

Pudendal (PUD) efferent activity contracts urethral rhabdosphincters to resist urine leakage. This study evaluates the potential for PUD nerve stimulation to provide benefit for urinary incontinence. Acute responses of the urethral rhabdosphincter to modulation of current amplitude, pulse duration (PD), and frequency of stimulation were examined. Urethral pressure was measured using a microtip catheter in chloralose-anesthetized, male cats with or without acute spinalization at T10. Stimulation was applied from an external pulse generator coupled to cuff electrodes placed around left and right PUD nerves in the ischiorectal fossa, central to its branching. Bladder pressure clamp techniques were used for testing effects of stimulation on time and rate of leakage during PUD stimulation. Single pulses (0.1 ms) produced single transient increases in urethral pressure that peaked at 50 ms and diminished to 50% of peak at 90 ms. Threshold current was 88 ± 30μA with maximal responses occurring with 50% increases in current. Peak pressures increased with increasing PDs between 40–180μs. Summation, tetany, peak pressures, and fatigue of responses to increasing stimulation frequencies during 2 min periods of stimulation are described. Stimulation under pressures that are typical during bladder filling or during bladder contractions (30–40 cm H2O) prevented leakage up to an hour in some animals, increased the median time to leak from 0.3 min to 56.0 min, and decreased the median rate of leakage from 1.44 ml/min to 0.04 ml/min when leakage did occur in less than hour. During rapid elevations in bladder pressure to simulate a Valsalva-like bladder pressure (120 cm H2O), PUD stimulation increased the median time to leak from 9 s to 93 s and decreased the median rate of leakage from 5.5 ml/min to 3.4 ml/min. These results support future studies of bilateral PUD stimulation in a clinically-relevant, animal model of urinary incontinence.

Urethral pressure profile during ejaculation in men with spinal cord injury.

Ejaculation is often impaired in men with spinal cord injury (SCI). The aim of this prospective study was to assess sequence of sphincteric events and ejaculation dyssynergia during penile vibratory stimulation (PVS) in SCI men. Simultaneous recordings of bladder, bladder neck, prostate and external urethral sphincter pressures were performed using a microtip catheter with 5 pressure transducers. Between 2017 and 2019, ten men participated in the study for a total of 17 procedures. Antegrade ejaculation was found in three men with upper motor neuron (UMN) lesion. Ejaculation was preceded by a progressive increase in all urethral pressures, reaching sustained (plateau) or intermittent peaks above 220 cm H20. Antegrade ejaculation occurred after intermittent decreases in pressure at the external urethral sphincter level down to 100 cm H20, while the pressure at the bladder neck remained high (up to or above 220 cm H20). PVS was ineffective in eliciting ejaculation in seven men. In the five patients with UMN lesions, PVS elicited an increase in the external urethral sphincter pressure (mean 51 cm H20), while there was no pressure change in the two patients with lower motor neuron lesions. Due to lack of enough retrograde retrieval attempts, the hypothesis of ejaculatory dyssynergia could not be verified.

MP08-16 LOW PRESSURE VOIDING INDUCED BY PUDENDAL NERVE STIMULATION AND BLOCK USING LEAD ELECTRODES IN CATS

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology (MP08)1 Sep 2021MP08-16 LOW PRESSURE VOIDING INDUCED BY PUDENDAL NERVE STIMULATION AND BLOCK USING LEAD ELECTRODES IN CATS Jialiang Chen, Jianan Jian, Jicheng Wang, Zhijun Shen, Bing Shen, William Wang, Jonathan Beckel, William C de Groat, Christopher Chermansky, and Changfeng Tai Jialiang ChenJialiang Chen More articles by this author , Jianan JianJianan Jian More articles by this author , Jicheng WangJicheng Wang More articles by this author , Zhijun ShenZhijun Shen More articles by this author , Bing ShenBing Shen More articles by this author , William WangWilliam Wang More articles by this author , Jonathan BeckelJonathan Beckel More articles by this author , William C de GroatWilliam C de Groat More articles by this author , Christopher ChermanskyChristopher Chermansky More articles by this author , and Changfeng TaiChangfeng Tai More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001981.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We have previously shown that detrusor sphincter dyssynergia (DSD) in spinal cord injured (SCI) cats can be blocked with high frequency, biphasic, bilateral stimulation of the pudendal nerves using cuff electrodes. Also, we showed that combining this block with lower frequency (30 Hz) unilateral pudendal nerve stimulation (PNS) resulted in low-pressure (≤50 cmH2O) voiding in SCI cats. In this experiment, we sought to determine whether wire lead electrodes could be used to block and stimulate the pudendal nerve in spinal intact cats to achieve low-pressure voiding. METHODS: In anesthetized cats, wire lead electrodes were placed on both pudendal nerves. High frequency biphasic stimulation (1 kHz) was applied to block the nerve while 30 Hz stimulus pulses (0.2 ms) applied by a separate lead electrode located proximally on the nerve was used to elicit contractions of the external urethral sphincter (EUS) or induce a reflex bladder contraction. In 4 cats, a catheter was inserted into the distal urethra to perfuse and measure the increase in urethral pressure (IUP) caused by EUS contraction. In another 4 cats, intravesical pressure was measured via a catheter inserted into the bladder dome. RESULTS: The 1 kHz stimulation (30-60 secs, 0.5-5 mA) produced a complete post-stimulation block of PNS evoked IUP for ≥2 mins (see figure 1) and a partial block lasting 6-18 minutes. The block duration lengthened after increasing either the intensity or duration of the kHz stimulation. Without the 1 kHz block, 30 Hz stimulation alone induced high-pressure (90 cmH2O) voiding (see figure 2). When combined with the 1 kHz block, the 30 Hz stimulation induced low-pressure (≤50 cmH2O) voiding with a voiding efficiency of 80%. CONCLUSIONS: This study demonstrated that the pudendal nerve can be successfully blocked by a lead electrode. Furthermore, combining 1 kHz PNS, which blocks EUS contractions, and 30 Hz PNS, which stimulates the bladder, results in low-pressure voiding that is highly efficient. Source of Funding: Bridging the Gap Plus (BG+) program of DARPA under contract N66001-20-C-4050 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e156-e157 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jialiang Chen More articles by this author Jianan Jian More articles by this author Jicheng Wang More articles by this author Zhijun Shen More articles by this author Bing Shen More articles by this author William Wang More articles by this author Jonathan Beckel More articles by this author William C de Groat More articles by this author Christopher Chermansky More articles by this author Changfeng Tai More articles by this author Expand All Advertisement Loading ...

Targeted neuromodulation of pelvic floor nerves in aging and multiparous rabbits improves continence

Pelvic floor muscle stretch injury during pregnancy and birth is associated with the incidence of stress urinary incontinence (SUI), a condition that affects 30–60% of the female population and is characterized by involuntary urine leakage during physical activity, further exacerbated by aging. Aging and multiparous rabbits suffer pelvic nerve and muscle damage, resulting in alterations in pelvic floor muscular contraction and low urethral pressure, resembling SUI. However, the extent of nerve injury is not fully understood. Here, we used electron microscopy analysis of pelvic and perineal nerves in multiparous rabbits to describe the extent of stretch nerve injury based on axon count, axon size, myelin-to-axon ratio, and elliptical ratio. Compared to young nulliparous controls, mid-age multiparous animals showed an increase in the density of unmyelinated axons and in myelin thickness in both nerves, albeit more significant in the bulbospongiosus nerve. This revealed a partial but sustained damage to these nerves, and the presence of some regenerated axons. Additionally, we tested whether electrical stimulation of the bulbospongiosus nerve would induce muscle contraction and urethral closure. Using a miniature wireless stimulator implanted on this perineal nerve in young nulliparous and middle age multiparous female rabbits, we confirmed that these partially damaged nerves can be acutely depolarized, either at low (2–5 Hz) or medium (10–20 Hz) frequencies, to induce a proportional increase in urethral pressure. Evaluation of micturition volume in the mid-age multiparous animals after perineal nerve stimulation, effectively reversed a baseline deficit, increasing it 2-fold (p = 0.02). These results support the notion that selective neuromodulation of pelvic floor muscles might serve as a potential treatment for SUI.

Secretomes of human pluripotent stem cell-derived smooth muscle cell progenitors upregulate extracellular matrix metabolism in the lower urinary tract and vagina

BackgroundAdult mesenchymal stem cells (MSCs) have been studied extensively for regenerative medicine; however, they have limited proliferation in vitro, and the long culture time induces cell senescence. MSCs also contribute to tissue repair through their paracrine function. In this study, we sought to examine the paracrine effects of human smooth muscle cell progenitors (pSMC) on the urethra and adjacent vagina of stress urinary incontinence rodents. We use human pluripotent stem cell (PSC) lines to derive pSMCs to overcome the issue of decreased proliferation in tissue culture and to obtain a homogenous cell population.MethodThree human PSC lines were differentiated into pSMCs. The conditioned medium (CM) from pSMC culture, which contain pSMC secretomes, was harvested. To examine the effect of the CM on the extracellular matrix of the lower urinary tract, human bladder smooth muscle cells (bSMCs) and vaginal fibroblasts were treated with pSMC-CM in vitro. Stress urinary incontinence (SUI) was induced in rats by surgical injury of the urethra and adjacent vagina. SUI rats were treated with pSMC-CM and monitored for 5 weeks. Urethral pressure testing was performed prior to euthanasia, and tissues were harvested for PCR, Western blot, and histological staining. Kruskal-Wallis one-way ANOVA test and Student t test were used for statistical comparisons.ResultspSMC-CM upregulated MMP-2, TIMP-2, collagen, and elastin gene expression, and MMP-9 activity in the human bladder and vaginal cells consistent with elastin metabolism modulation. pSMC-CM treatment in the SUI rat improved urethral pressure (increase in leak point pressure compared to intact controls, p < 0.05) and increased collagen and elastin expression in the urethra and the adjacent vagina.ConclusionConditioned media from smooth muscle cell progenitors derived from human pluripotent stem cells improved urethral leak point pressure and collagen and elastin content in the SUI rat. These findings suggest a novel therapeutic potential for PSC-based treatments for SUI and pelvic floor disorders where tissues are affected by collagen, elastin, and smooth muscle loss.

Novel insight into pressurization of the male and female urethra through application of a multi-channel fibre-optic pressure transducer: Proof of concept and validation.

PurposeTo confirm feasibility of recording pressure along the length of the urethra using a multi-sensor fibre-optic pressure catheter; to identify the spatial and temporal features of changes in pressure along the urethra at sites related to specific striated pelvic floor muscles; and to investigate the relationship between urethral pressures and activation of individual pelvic floor muscles estimated from ultrasound imaging.Materials and MethodsProof-of-concept study including one male (47 years old) and one female (33 years old). A multi-sensor fibre optic pressure catheter (10 mm sensor separation) was inserted into the urethra. Pressure data were recorded simultaneously with trans-perineal ultrasound imaging measures of pelvic floor muscle activity during sub-maximal and maximal voluntary contractions and evoked coughs.ResultsPressure changes along the urethra were recorded in all tasks in both participants. Face validity of interpretation of pressure measures with respect to individual muscles was supported by correlation with ultrasound-measured displacements induced by the relevant muscles. Onset of pressure increase occurred in a distal to proximal sequence in the urethra of the male but not the female during voluntary contraction. Peak urethral pressures varied in location, timing and amplitude between tasks. Evoked cough induced in the greatest urethral pressure increase across all tasks for both participants.ConclusionsThe high spatial resolution pressure catheter provide viable and valid recordings of urethral pressure in a male and female. Data provide preliminary evidence of sex differences in spatial and temporal distribution of urethral pressure changes.

Eficiencia de los ejercicios de Kegel, evaluada con estudio urodinámico en pacientes con incontinencia urinaria

Antecedentes: La incontinencia urinaria se define como la queja por pérdida involuntaria de orina. La International Consultation on Incontinence (ici) estima de 25 a 45% de prevalencia de incontinencia urinaria (iu) a nivel mundial. Dentro de su manejo clínico se incluyen los ejercicios de Kegel para incrementar la fuerza del cierre uretral; sin embargo, la literatura reporta una mala técnica en la realización de estos ejercicios en 25% de la población, lo que genera un peor pronóstico en la historia natural de la enfermedad. El objetivo del estudio es valorar la eficacia de los ejercicios de Kegel en población con iu midiendo la respuesta en la presión uretral.&#x0D; Materiales y métodos: Estudio observacional prospectivo. Se enrolaron un total de 38 pacientes al estudio, se recabaron variables demográficas y se brindó una explicación de los ejercicios durante cinco minutos. Se midió la presión de cierre uretral máximo (pcum) y presión uretral (pu) hasta el punto de presión funcional del esfínter uretral y, posterior a la realización de maniobra de Kegel, se revisó si el paciente elevó su pcum.&#x0D; Resultados: De 38 pacientes, solo 52% alcanzó una elevación de la pu con ejercicios de Kegel. Se encontró una falta de respuesta a los ejercicios en pacientes con sobrepeso (p= 0.015).&#x0D; Conclusión: La realización de los ejercicios de Kegel tiene una respuesta limitada en pacientes con incontinencia urinaria, además de ausencia de efectividad en la pu de pacientes con sobrepeso.

Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

Canine urethral sphincter pressure profile under incremental inflation of an artificial cuff: a cadaver study.

To determine whether artificial urethral sphincter filling volume is proportional to peak pressure exerted on the urethra. Urethral pressure profilometry was performed in five female, medium-sized, mixed-breed canine cadavers following artificial urethral sphincter placement. Maximum urethral pressure was recorded following sequential incremental inflation of 0.15 mL and compared to baseline pressure and between dogs using two-way analysis of variance. Artificial urethral sphincter placement in cadavers was associated with an increase in urethral pressure, which was significantly correlated with inflation volume. The correlation was non-linear and demonstrated considerable individual variation. Maximum urethral pressures after artificial urethral sphincter placement exceeded those reported in conscious continent dogs within a narrow volume range, in which a 0.15 mL infusion more than doubled maximal urethral pressures. Rapid increases in urethral pressure from the artificial urethral sphincter over a small range of filling volumes (0.15 mL increments) might explain why some clinical cases can become suddenly dysuric following incremental inflations. We suggest that smaller increments of filling (0.05to 0.1mL) may achieve finer pressure control.

Midurethral support is also necessary for reflex closure of the urethra.

The pathophysiology of female stress urinary incontinence (SUI) is far from unraveled. Capturing all aspects of this bothersome condition in one theory remains challenging. The well-known Hammock and Integral theories, both from the early 90's, were successful in explaining a large proportion of the observations made in clinical practice. Nevertheless, some (pre)clinical observations cannot be explained by the current understanding. One of the issues concerns the pressure transmission. Is this process really a passive mechanical action, or is an additional active mechanism responsible for urethral closure? The finding that an increase in urethral pressure sometimes precedes and exceeds the increase in intravesical pressure suggests the latter. This concept has never been incorporated in one of the existing theories describing SUI. This is remarkable as a lot of evidence has been generated in recent years that proves involvement of active components. This review aims to provide an additional theory in which an active reflex closure mechanism of the urethra is incorporated. Recent as well as older publications from clinical and animal studies are included to support the hypothesis. The smooth muscles of the urethra, the vascular bed, and the estrogen-influenced urethral mucosa, combined with striated muscle tone, contribute to the intra-urethral pressure. A passive transmission of force to the urethra exists only in the abdominal proximal third of the urethra. In the distal two thirds of the urethra an active closure mechanism is present, dependent on sufficient urethral support in the proper anatomical position. This active closure mechanism is generated by reflex contraction of striated muscles of the urethra and the pelvic floor. Continence is a result of passive as well as active urethral closure mechanisms. The most important factor in female continence seems to be the proper functioning of an active reflex urethral closing mechanism.

Urethral function and histopathology in aged female rats as a stress urinary incontinence model.

Stress urinary incontinence (SUI) is a common disease condition in elderly women, suggesting that its etiology may be linked to aging. To investigate the hypothesis that urethral dysfunction and histopathological changes are possible contributors to SUI in elderly women, several parameters of urethral function, as well as histological parameters, were compared between young and aged rats. Virgin female rats were examined at 3 different ages, namely 3, 12, and 24 months, corresponding to young, middle-aged, and aged rats, respectively. Urethral function was assessed by measuring the leak point pressure (LPP), pudendal nerve stimulation (PNS)-induced elevation in urethral pressure, and phenylephrine-induced increase in urethral perfusion pressure (UPP). Histopathological assessments were performed following hematoxylin and eosin (HE), Masson's trichrome, and immunofluorescence staining of urethral tissue. LPP of aged rats was significantly reduced compared to that of both young and middle-aged rats. PNS-induced elevation in urethral pressure in aged rats was also significantly lower than that in young rats. In contrast, there were no significant differences in the phenylephrine-induced increase in UPP between young and aged rats. Connective tissue area in the external urethral sphincter (EUS) layer was increased in aged rats, whereas the smooth muscle layer was histologically similar to that in young rats. The number of EUS fibers was significantly reduced in aged rats, whereas the cross-sectional area of EUS fibers increased from differed compared with young rats. We have demonstrated age-related changes in EUS function and morphology in the rat urethra, which are considered to be etiological risk factors for SUI in humans.

Effects of an alpha1A/D-adrenoceptor antagonist, naftopidil, and a phosphodiesterase type 5 inhibitor, tadalafil, on urinary bladder remodeling in rats with spinal cord injury.

In order to clarify whether an alpha1A/D-adrenoceptor (α1 A/D-AR) antagonist, naftopidil, or a phosphodiesterase type 5 (PDE5) inhibitor, tadalafil, prevents bladder wall remodeling after spinal cord injury (SCI), we examined the bladder and urethral activity as well as ischemic and fibrotic changes in the bladder using SCI rats with or without naftopidil or tadalafil treatment. Adult female Sprague-Dawley rats were divided into four groups: (1) normal (spinal cord intact); (2) vehicle SCI; (3) naftopidil SCI; and (4) tadalafil SCI groups. In SCI groups, rats underwent Th9-10 spinal cord transection followed by oral application of vehicle, naftopidil (20 mg/kg/day) or tadalafil (2 mg/kg/day) for 1, 2, 4, 8, and 12 weeks. Bladder and urethral pressures, mRNA levels of fibrosis-related molecules and ischemia markers and the composition of bladder collagen and elastin were evaluated. Naftopidil treatment reduced the upregulation of mRNA levels of ischemia and fibrosis markers at the early phase of SCI, and ameliorated the decrease of bladder compliance and voiding efficiency, and the increase of urethral pressure and collagen concentration in the bladder wall at the late phase of SCI. Tadalafil treatment reduced the upregulation of mRNA levels of fibrosis markers, the decrease of bladder compliance and the increase of collagen concentration at the late phase of SCI. These results suggest that naftopidil and tadalafil treatments improved the bladder remodeling shown by increased bladder collagen contents after SCI in a different time course. Thus, these treatments could be effective for reducing the SCI-related tissue remodeling in the bladder. Neurourol. Urodynam. 9999:XX-XX, 2016. © 2016 Wiley Periodicals, Inc.

Cell versus Chemokine Therapy in a Nonhuman Primate Model of Chronic Intrinsic Urinary Sphincter Deficiency

Mixed efficacy results of autologous skeletal muscle precursor cell therapy in women with chronic intrinsic urinary sphincter deficiency have increased interest in the therapeutic value of alternative regenerative medicine approaches. The goal of this study was to compare the effects of the cell homing chemokine CXCL12 (C-X-C motif chemokine 12) and skeletal muscle precursor cells on chronic urinary sphincter regeneration in chronic intrinsic urinary sphincter deficiency. Five million autologous skeletal muscle precursor cells or 100 ng CXCL12 were injected in the urinary sphincter complex of adult female cynomolgus monkeys with chronic (6-month history) intrinsic urinary sphincter deficiency. These treatment groups of 3 monkeys per group were compared to a group of 3 with no intrinsic urinary sphincter deficiency and no injection, and a group of 3 with intrinsic urinary sphincter deficiency plus vehicle injection. Maximal urethral pressure was measured at rest, during stimulation of the urinary sphincter pudendal nerves at baseline and again 6 months after treatment. The monkeys were then necropsied. The urinary sphincters were collected for tissue analysis of muscle and collagen content, vascularization and motor endplates. CXCL12 but not skeletal muscle precursor cells increased resting maximal urethral pressure in nonhuman primates with chronic intrinsic urinary sphincter deficiency compared to that in monkeys with intrinsic urinary sphincter plus vehicle injection (p >0.05). Skeletal muscle precursor cells and CXCL12 only partially restored pudendal nerve stimulated increases in maximal urethral pressure (p >0.05), sphincter vascularization and motor endplate expression in monkeys with chronic intrinsic urinary sphincter deficiency. Additionally, CXCL12 but not skeletal muscle precursor cell injections decreased collagen and increased the muscle content of urinary sphincter complex in monkeys with chronic intrinsic urinary sphincter deficiency compared to those with intrinsic urinary sphincter plus vehicle injection and no intrinsic urinary sphincter plus no injection (p <0.05 and >0.05, respectively). These results raise questions about cell therapy for chronic intrinsic urinary sphincter deficiency and identify a chemokine treatment (CXCL12) as a potential alternative treatment of chronic intrinsic urinary sphincter deficiency.

Maximum Urethral Closure Pressure Increases After Successful Adjustable Continence Therapy (ProACT) for Stress Urinary Incontinence After Radical Prostatectomy

To evaluate changes of the urethral pressure profile (UPP) after implantation of adjustable continence therapy (ProACT), a minimally invasive procedure in which 2 volume-adjustable balloons are placed periurethrally for treatment of male stress urinary incontinence. The working mechanism of the ProACT to achieve continence has not been fully understood. We hypothesized that successful treatment with ProACT improves urinary continence by inducing a significant increase in static urethral pressure. We included patients who underwent UPP before and after ProACT implantation. UPPs were initially performed with the Brown-Wickham water perfusion method and later with the T-DOC Air-Charged catheter method. Pre- and postoperative UPPs and International Prostate Symptom Scores were evaluated. UPP measurements of successfully (no or 1 precautionary pad per day) and unsuccessfully treated patients were compared. Twenty-seven patients were included in the study; 23 patients were successfully and 4 patients were unsuccessfully treated. Maximum urethral closure pressure (MUCP) increased significantly from median 58.0 to 79.0 cmH2O in the successfully treated group (P = .001). Within the subgroup of unsuccessfully treated patients, MUCP did not change significantly (P = .715). The change in MUCP was statistically significantly different between the successful and unsuccessful group (P = .034). Total score of the International Prostate Symptom Scores did not change significantly after ProACT implantation (P = .097). Successful treatment with ProACT is associated with a significant increase of MUCP. This implies that increased static urethral pressure contributes to the working mechanism of the ProACT device to achieve continence.

Triple therapy with Lactobacilli acidophili, estriol plus pelvic floor rehabilitation for symptoms of urogenital aging in postmenopausal women

To assess the effects of the combination of pelvic floor rehabilitation, intravaginal estriol and Lactobacillus acidophli administration on stress urinary incontinence (SUI), urogenital atrophy and recurrent urinary tract infections in postmenopausal women. 136 postmenopausal women with urogenital aging symptoms were enrolled in this prospective randomized study. randomly divided into two groups and each group consisted of 68 women. Subjects in the triple therapy (group I) received 1 intravaginal ovule containing 30 mcg estriol and Lactobacilli acidophili (50 mg lyophilisate containing at least 100 million live bacteria) such as once daily for 2 weeks and then two ovules once weekly for a total of 6 months as maintenance therapy plus pelvic floor rehabilitation. Subjects in the group II received one intravaginal estriol ovule (1 mg) plus pelvic floor rehabilitation in a similar regimen. We evaluated urogenital symptomatology, urine cultures, colposcopic findings, urethral cytologic findings, urethral pressure profiles and urethrocystometry before, as well as after 6 months of treatment. After therapy, the symptoms and signs of urogenital atrophy significantly improved in both groups. 45/59 (76.27%) of the group I and 26/63 (41.27%) of the group II referred a subjective improvement of their incontinence. In the patients treated by triple therapy with lactobacilli, estriol plus pelvic floor rehabilitation, we observed significant improvements of colposcopic findings, and there were statistically significant increases in mean maximum urethral pressure, in mean urethral closure pressure, as well as in the abdominal pressure transmission ratio to the proximal urethra. Our results showed that triple therapy with L. acidophili, estriol plus pelvic floor rehabilitation was effective and should be considered as first-line treatment for symptoms of urogenital aging in postmenopausal women.

The role of pelvic and perineal striated muscles in urethral function during micturition in female rabbits

To evaluate the role of pelvic and perineal striated muscles on urethral function during micturition. Pubococcygeus, or both bulbospongiosus and ischiocavernosus muscles were electrically stimulated during the voiding phase of micturition, and bladder and urethral pressure were simultaneously recorded in urethane anesthetized female rabbits. Bladder and urethral function were assessed measuring urodynamic and urethral pressure variables obtained before and during the stimulation of muscles. Two-tail paired t-tests were carried out in order to determine significant differences (P < 0.05) between groups. Electric stimulation of the pubococcygeus during voiding decreased voiding efficiency and voided volume, whereas residual volume, the duration of voiding, the interval between bladder contraction and urethral resistance increased. Simultaneously, there was an increase in maximum urethral pressure, as well as an increase in the pressure to return to baseline and in the pressure required to close the urethra. Electrical stimulation of bulbospongiosus and ischiocavernosus muscles increased voiding efficiency, voiding duration, and the maximal pressure in bladder. Meanwhile, the maximal urethral pressure, the time related to the rise of urethral pressure, and the urethral pressure required to close the urethra decreased. The stimulation of pelvic and perineal muscles have opposing roles in urethral function during micturition. Pubococcygeus muscles facilitate urethral closure, while they inhibit bladder contraction. In contrast, bulbospongiosus and ischiocavernosus muscles prevent urethral contraction while they promote bladder contraction.

A Nonhuman Primate Model of Stable Urinary Sphincter Deficiency

The pathophysiology of urinary sphincter deficiency in women remains incompletely understood and current treatment options have limitations. Female nonhuman primates may represent a relevant animal model for studies of pathophysiology and treatment interventions because of their human-like reproductive and age associated stages of life (premenopause, perimenopause and postmenopause), lower urinary tract structure and bipedal posture. We developed and characterized a nonhuman primate model of defined injury to the urethral sphincter complex. We used 22 adult female cynomolgus monkeys in which injury to the sphincter complex was created by cauterizing and then transecting its pudendal innervation. Urodynamic studies were performed before and during pudendal and hypogastric nerve stimulation at baseline, and 3, 6 and 12 months after injury. We also analyzed sphincter structure in vivo by cystourethrography, and ex vivo by quantitative histology and immunohistochemistry at these time points. Injury produced a 47% to 50% decrease in maximal urethral pressure (vs baseline p <0.05). It also abolished the increase in maximal urethral pressure in response to pudendal and hypogastric nerve stimulation (vs baseline p >0.05), which persisted more than 12 months after injury. Urodynamic changes were consistent with decreased skeletal and smooth muscle content, decreased nerve responses and an associated decrease in somatic and adrenergic innervation in the sphincter complex. These structural and urodynamic changes are consistent with those in patients with stress urinary incontinence. They support the usefulness of nonhuman primates as translatable surrogates for pathophysiological studies of urinary sphincter deficiency and testing novel therapies for that condition.