Proper understanding of recurrent stress urinary incontinence treatment in women (PURSUIT): a randomised controlled trial of endoscopic and surgical treatment.

BACKGROUND: Women with stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently, the interventional treatments for SUI are surgical, or endoscopic bulking injection(s). However, these procedures are not always successful, and symptoms can persist or come back after treatment, categorised as recurrent SUI. There are longstanding symptoms and distress associated with a failed primary treatment, and currently, there is no consensus on how best to treat women with recurrent, or persistent, SUI. METHODS: A two-arm trial, set in at least 20 National Health Service (NHS) urology and urogynaecology referral units in the UK, randomising 250 adult women with recurrent or persistent SUI 1:1 to receive either an endoscopic intervention (endoscopic bulking injections) or a standard NHS surgical intervention, currently colposuspension, autologous fascial sling or artificial urinary sphincter. The aim of the trial is to determine whether surgical treatment is superior to endoscopic bulking injections in terms of symptom severity at 1 year after randomisation. This primary outcome will be measured using the patient-reported International Consultation on Incontinence Questionnaire - Urinary Incontinence - Short Form (ICIQ-UI-SF). Secondary outcomes include assessment of longer-term clinical impact, improvement of symptoms, safety, operative assessments, sexual function, cost-effectiveness and an evaluation of patients' and clinicians' views and experiences of the interventions. DISCUSSION: There is a lack of high-quality, randomised, scientific evidence for which treatment is best for women presenting with recurrent SUI. The PURSUIT study will benefit healthcare professionals and patients and provide robust evidence to guide further treatment and improve symptoms and quality of life for women with this condition. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) registry ISRCTN12201059. Registered on 09 January 2020.

Female Urgency, Trial of Urodynamics as Routine Evaluation (FUTURE study): a superiority randomised clinical trial to evaluate the effectiveness and cost-effectiveness of invasive urodynamic investigations in management of women with refractory overactive bladder symptoms.

BACKGROUND: Overactive bladder (OAB) syndrome is a symptom complex affecting 12-14% of the UK adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. OAB has a negative impact on women's social, physical, and psychological wellbeing. Initial treatment includes lifestyle modifications, bladder retraining, pelvic floor exercises and pharmacological therapy. However, these measures are unsuccessful in 25-40% of women (refractory OAB). Before considering invasive treatments, such as Botulinum toxin injection or sacral neuromodulation, most guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity (DO). However, urodynamics may fail to show evidence of DO in up to 45% of cases, hence the need to evaluate its effectiveness and cost-effectiveness. FUTURE (Female Urgency, Trial of Urodynamics as Routine Evaluation) aims to test the hypothesis that, in women with refractory OAB, urodynamics and comprehensive clinical assessment is associated with superior patient-reported outcomes following treatment and is more cost-effective, compared to comprehensive clinical assessment only. METHODS: FUTURE is a pragmatic, multi-centre, superiority randomised controlled trial. Women aged ≥ 18 years with refractory OAB or urgency predominant mixed urinary incontinence, and who have failed/not tolerated conservative and medical treatment, are considered for trial entry. We aim to recruit 1096 women from approximately 60 secondary/tertiary care hospitals across the UK. All consenting women will complete questionnaires at baseline, 3 months, 6 months and 15 months post-randomisation. The primary outcome is participant-reported success at 15 months post-randomisation measured using the Patient Global Impression of Improvement. The primary economic outcome is incremental cost per quality-adjusted life year gained at 15 months. The secondary outcomes include adverse events, impact on other urinary symptoms and health-related quality of life. Qualitative interviews with participants and clinicians and a health economic evaluation will also be conducted. The statistical analysis of the primary outcome will be by intention-to-treat. Results will be presented as estimates and 95% CIs. DISCUSSION: The FUTURE study will inform patients, clinicians and policy makers whether routine urodynamics improves treatment outcomes in women with refractory OAB and whether it is cost-effective. TRIAL REGISTRATION: ISRCTN63268739 . Registered on 14 September 2017.

The effect of consultant outcome publication on surgeon behaviour: a systematic review and narrative synthesis.

Introduction Surgeon-specific outcome data, or consultant outcome publication, refers to public access to named surgeon procedural outcomes. Consultant outcome publication originates from cardiothoracic surgery, having been introduced to US and UK surgery in 1991 and 2005, respectively. It has been associated with an improvement in patient outcomes. However, there is concern that it may also have led to changes in surgeon behaviour. This review assesses the literature for evidence of risk-averse behaviour, upgrading of patient risk factors and cessation of low-volume or poorly performing surgeons. Materials and methods A systematic literature review of Embase and Medline databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Original studies including data on consultant outcome publication and its potential effect on surgeon behaviour were included. Results Twenty-five studies were identified from the literature search. Studies suggesting the presence of risk-averse behaviour and upgrading of risk factors tended to be survey based, with studies contrary to these findings using recognised regional and national databases. Discussion and conclusion Our review includes instances of consultant outcome publication leading to risk-averse behaviour, upgrading of risk factors and cessation of low-volume or poorly performing surgeons. As UK data on consultant outcome publication matures, further research is essential to ensure that high-risk patients are not inappropriately turned down for surgery.

Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS).

BACKGROUND: Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners. METHODS: A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners. DISCUSSION: This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life. TRIAL REGISTRATION: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869.

Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial.

BACKGROUND: Lower urinary tract symptoms (LUTS) comprise storage symptoms, voiding symptoms and post-voiding symptoms. Prevalence and severity of LUTS increase with age and the progressive increase in the aged population group has emphasised the importance to our society of appropriate and effective management of male LUTS. Identification of causal mechanisms is needed to optimise treatment and uroflowmetry is the simplest non-invasive test of voiding function. Invasive urodynamics can evaluate storage function and voiding function; however, there is currently insufficient evidence to support urodynamics becoming part of routine practice in the clinical evaluation of male LUTS. DESIGN: A 2-arm trial, set in urology departments of at least 26 National Health Service (NHS) hospitals in the United Kingdom (UK), randomising men with bothersome LUTS for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry and a care pathway based on non-invasive routine tests. The aim of the trial is to determine whether a care pathway not including invasive urodynamics is no worse for men in terms of symptom outcome than one in which it is included, at 18 months after randomisation. This primary clinical outcome will be measured with the International Prostate Symptom Score (IPSS). We will also establish whether inclusion of invasive urodynamics reduces rates of bladder outlet surgery as a main secondary outcome. DISCUSSION: The general population has an increased life-expectancy and, as men get older, their prostates enlarge and potentially cause benign prostatic obstruction (BPO) which often requires surgery. Furthermore, voiding symptoms become increasingly prevalent, some of which may not be due to BPO. Therefore, as the population ages, more operations will be considered to relieve BPO, some of which may not actually be appropriate. Hence, there is sustained interest in the diagnostic pathway and this trial could improve the chances of an accurate diagnosis and reduce overall numbers of surgical interventions for BPO in the NHS. The morbidity, and therapy costs, of testing must be weighed against the cost saving of surgery reduction. TRIAL REGISTRATION: Controlled-trials.com - ISRCTN56164274 (confirmed registration: 8 April 2014).

Physiological and pathophysiological implications of micromotion activity in urinary bladder function.

'Micromotions' is a term signifying the presence of localized microcontractions and microelongations, alongside non-motile areas. The motile areas tend to shift over the bladder surface with time, and the intravesical pressure reflects moment-by-moment summation of the interplay between net contractile force generated by micromotions and general bladder tone. Functionally, the bladder structure may comprise modules with variable linkage, which supports presence of localized micromotions (no functional linkage between modules), propagating contractions (where emergence of linkage allows sequential activation) and the shifting of micromotions over time. Detrusor muscle, interstitial cells and intramural innervation have properties potentially relevant for initiating, coordinating and modulating micromotions. Conceptually, such activity could facilitate the generation of afferent activity (filling state reporting) in the absence of intravesical pressure change and the ability to transition to voiding at any bladder volume. This autonomous activity is an intrinsic property, seen in various experimental contexts including the clinical setting of human (female) overactive bladder. 'Disinhibited autonomy' may explain the obvious micromotions in isolated bladders and perhaps contribute clinically in neurological disease causing detrusor overactivity. Furthermore, any process that could increase the initiation or propagation of microcontractions might be anticipated to have a functional effect, increasing the likelihood of urinary urgency and detrusor overactivity respectively. Thus, models of bladder outlet obstruction, neurological trauma and ageing provide a useful framework for detecting cellular changes in smooth muscle, interstitial cells and innervation, and the consequent effects on micromotions.

Tamsulosin/solifenacin fixed-dose combination tablet for the treatment of male lower urinary tract symptoms.

Men reporting mixed storage and voiding lower urinary tract symptoms (LUTS) often experience persisting storage LUTS after initial treatment. Combination therapy of an alpha-adrenergic antagonist and an antimuscarinic is increasingly recognized as a therapy option. Clinical trials have combined tamsulosin (0.4 mg) with different doses of solifenacin. In the SATURN study, greater efficacy benefits were observed for moderate to severe storage symptoms. Single tablet administration may offer improved compliance. Accordingly, the NEPTUNE study researched fixed-dose combination (FDC) therapy for mixed LUTS, using tamsulosin (oral controlled administration system formulation), with solifenacin (6 or 9 mg). The FDC containing tamsulosin and solifenacin 6 mg improved storage and voiding LUTS, with no additional benefit from the higher solifenacin dose. During the open-label extension study, symptom improvement was maintained. Adverse events reflected the known effects of the component therapies. Acute urinary retention, an adverse event of special interest, was seen in only a small number of treated men.

An artificial model for studying fluid dynamics in the obstructed and stented ureter.

Fluid dynamics in the obstructed and stented ureter represents a non-trivial subject of investigation since, after stent placement, the urine can flow either through the stent lumen or in the extra-luminal space located between the stent wall and the ureteric inner wall. Fluid dynamic investigations can help understanding the phenomena behind stent failure (e.g. stent occlusions due to bacterial colonization and encrustations), which may cause kidney damage due to the associated high pressures generated in the renal pelvis. In this work a microfluidic-based transparent device (ureter model, UM) has been developed to simulate the fluid dynamic environment in a stented ureter. UM geometry has been designed from measurements on pig ureters. Pressure in the renal pelvis compartment has been measured against three variables: fluid viscosity (µ), volumetric flow rate (Q) and level of obstruction (OB%). The measurements allowed a quantification of the critical combination of µ, Q and OB% values which may lead to critical pressure levels in the kidney. Moreover, an example showing the possibility of applying particle image velocimetry (PIV) technology to the developed microfluidic device is provided.

A first-principles characterization of water adsorption on forsterite grains.

Numerical simulations examining chemical interactions of water molecules with forsterite grains have demonstrated the efficacy of nebular gas adsorption as a viable mechanism for water delivery to the terrestrial planets. Nevertheless, a comprehensive picture detailing the water-adsorption mechanisms on forsterite is not yet available. Towards this end, using accurate first-principles density functional theory, we examine the adsorption mechanisms of water on the (001), (100), (010) and (110) surfaces of forsterite. While dissociative adsorption is found to be the most energetically favourable process, two stable associative adsorption configurations are also identified. In dual-site adsorption, the water molecule interacts strongly with surface magnesium and oxygen atoms, whereas single-site adsorption occurs only through the interaction with a surface Mg atom. This results in dual-site adsorption being more stable than single-site adsorption.

Observational study comparing non-invasive blood pressure measurement at the arm and ankle during caesarean section.

Upper-arm non-invasive blood pressure measurement during caesarean section can be uncomfortable and unreliable because of movement artefact in the conscious parturient. We aimed to determine whether ankle blood pressure measurement could be used instead in this patient group by comparing concurrent arm and ankle blood pressure measured throughout elective caesarean section under regional anaesthesia in 64 term parturients. Bland-Altman analysis of mean difference (95% limits of agreement [range]) between the ankle and arm was 11.2 (-20.3 to +42.7 [-67 to +102]) mmHg for systolic arterial pressure, -0.5 (-21.0 to +19.9 [-44 to +91]) mmHg for mean arterial pressure and -3.8 (-25.3 to +17.8 [-41 to +94]) mmHg for diastolic arterial pressure. Although ankle blood pressure measurement is well tolerated and allows greater mobility of the arms than measurement from the arm, the degree of discrepancy between the two sites is unacceptable to allow routine use of ankle blood pressure measurement, especially for systolic arterial pressure. However, ankle blood pressure measurement may be a useful alternative in situations where arm blood pressure measurement is difficult or impossible.

Guías EAU sobre incontinencia urinaria / EAU Guidelines on Urinary Incontinence

Contexto: Las primeras directrices sobre incontinencia de la European Association of Urology (EAU) se publicaron en 2001. Dichas directrices se han actualizado con regularidad en los últimos años. Objetivo: El objetivo de este artículo es ofrecer un resumen de la actualización de las directrices sobre incontinencia urinaria (IU) de la EAU realizada en 2009. Recogida de evidencias: El comité de trabajo de la EAU formó parte de la IV Consulta Internacional sobre Incontinencia (ICI) y, con permiso de la ICI, llevó a cabo la extracción de la información de relevancia. La metodología de la IV ICI consistió en una amplia revisión de la literatura por parte de expertos internacionales y en la creación de un nivel de consenso. Asimismo, el nivel de evidencia se calificó de acuerdo con un sistema Oxford modificado y los grados de recomendación se atribuyeron en consonancia. Resumen de evidencias: Está disponible una versión completa de las directrices de la EAU sobre incontinencia urinaria en formato impreso (ampliada y en formato reducido), así como en formato de CD-ROM, pudiendo solicitarse a la oficina de la EAU o en línea en la dirección (http://www.uroweb.org/guidelines/online-guidelines/). La amplitud e invasividad de la evaluación de la IU depende de la gravedad y/o complejidad de los síntomas y signos clínicos, y es diferente para varones, mujeres, personas mayores de salud delicada, niños y pacientes con neuropatías. En el nivel de tratamiento inicial se aplican pruebas básicas de diagnóstico para descartar enfermedades o problemas subyacentes, tales como infecciones del tracto urinario. El tratamiento suele ser conservador (intervenciones en los hábitos de vida, fisioterapia, terapia física, farmacoterapia) y es de naturaleza empírica. En el nivel de tratamiento especializado (cuando haya fracasado la terapia inicial, ante un diagnóstico incierto o si los síntomas y señales son complejos o graves) suele ser necesaria una evaluación más elaborada, incluyendo técnica de imagen, endoscopia y urodinámica. Entre las opciones de tratamiento se incluyen intervenciones invasivas y la cirugía. Conclusiones: Las opciones de tratamiento de la IU están creciendo en número con rapidez, y estas guías de la EAU proporcionan una gradación de las evidencias (orientada por la medicina basada en la evidencia), así como una escala de recomendaciones para que la valoración sea la adecuada y las opciones de tratamiento estén en consonancia, aplicándose así una perspectiva clínica (AU)

Context: The first European Association of Urology (EAU) guidelines on incontinence were published in 2001. These guidelines were periodically updated in past years. Objective: The aim of this paper is to present a summary of the 2009 update of the EAU guidelines on urinary incontinence (UI). Evidence acquisition: The EAU working panel was part of the 4th International Consultation on Incontinence (ICI) and, with permission of the ICI, extracted the relevant data. The methodology of the 4th ICI was a comprehensive literature review by international experts and consensus formation. In addition, level of evidence was rated according to a modified Oxford system and grades of recommendation were given accordingly. Evidence summary: A full version of the EAU guidelines on urinary incontinence is available as a printed document (extended and short form) and as a CD-ROM from the EAU office or online from the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/). The extent and invasiveness of assessment of UI depends on severity and/or complexity of symptoms and clinical signs and is different for men, women, frail older persons, children, and patients with neuropathy. At the level of initial management, basic diagnostic tests are applied to exclude an underlying disease or condition such as urinary tract infection. Treatment is mostly conservative (lifestyle interventions, physiotherapy, physical therapy, pharmacotherapy) and is of an empirical nature. At the level of specialised management (when primary therapy failed, diagnosis is unclear, or symptoms and/or signs are complex/severe), more elaborate assessment is generally required, including imaging, endoscopy, and urodynamics. Treatment options include invasive interventions and surgery. Conclusions: Treatment options for UI are rapidly expanding. These EAU guidelines provide ratings of the evidence (guided by evidence-based medicine) and graded recommendations for the appropriate assessment and according treatment options and put them into clinical perspective (AU)

[EAU Guidelines on Urinary Incontinence]. / Guías EAU sobre incontinencia urinaria.

CONTEXT: The first European Association of Urology (EAU) guidelines on incontinence were published in 2001. These guidelines were periodically updated in past years. OBJECTIVE: The aim of this paper is to present a summary of the 2009 update of the EAU guidelines on urinary incontinence (UI). EVIDENCE ACQUISITION: The EAU working panel was part of the 4th International Consultation on Incontinence (ICI) and, with permission of the ICI, extracted the relevant data. The methodology of the 4th ICI was a comprehensive literature review by international experts and consensus formation. In addition, level of evidence was rated according to a modified Oxford system and grades of recommendation were given accordingly. EVIDENCE SUMMARY: A full version of the EAU guidelines on urinary incontinence is available as a printed document (extended and short form) and as a CD-ROM from the EAU office or online from the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/). The extent and invasiveness of assessment of UI depends on severity and/or complexity of symptoms and clinical signs and is different for men, women, frail older persons, children, and patients with neuropathy. At the level of initial management, basic diagnostic tests are applied to exclude an underlying disease or condition such as urinary tract infection. Treatment is mostly conservative (lifestyle interventions, physiotherapy, physical therapy, pharmacotherapy) and is of an empirical nature. At the level of specialised management (when primary therapy failed, diagnosis is unclear, or symptoms and/or signs are complex/severe),more elaborate assessment is generally required, including imaging, endoscopy, and urodynamics. Treatment options include invasive interventions and surgery. CONCLUSIONS: Treatment options for UI are rapidly expanding. These EAU guidelines provide ratings of the evidence (guided by evidence-based medicine) and graded recommendations for the appropriate assessment and according treatment options and put them into clinical perspective.

Neural control of the lower urinary and gastrointestinal tracts: supraspinal CNS mechanisms.

Normal urinary function is contingent upon a complex hierarchy of CNS regulation. Lower urinary tract afferents synapse in the dorsal horn of the spinal cord and ascend to the midbrain periaqueductal gray (PAG), with a separate nociception path to the thalamus. A spino-thalamo-cortical sensory pathway is present in some primates, including humans. In the brainstem, the pontine micturition center (PMC) is a convergence point of multiple influences, representing a co-ordinating center for voiding. Many PMC neurones have characteristics necessary to categorize the center as a pre-motor micturition nucleus. In the lateral pontine brainstem, a separate region has some characteristics to suggest a "continence center." Cerebral control determines that voiding is permitted if necessary, socially acceptable and in a safe setting. The frontal cortex is crucial for decision making in an emotional and social context. The anterior cingulate gyrus and insula co-ordinate processes of autonomic arousal and visceral sensation. The influence of these centers on the PMC is primarily mediated via the PAG, which also integrates bladder sensory information, thereby moderating voiding and storage of urine, and the transition between the two phases. The parabrachial nucleus in the pons is also important in behavioral motivation of waste evacuation. Lower urinary tract afferents can be modulated at multiple levels by corticolimbic centers, determining the interoception of physiological condition and the consequent emotional motor responses. Alterations in cognitive modulation, descending modulation, and hypervigilance are important in functional (symptom-based) clinical disorders.

Muscarinic stimulation of the mouse isolated whole bladder: physiological responses in young and ageing mice.

1 Peripheral autonomous bladder activity is an incompletely understood property that may be important both in normal bladder function and in functional problems of the lower urinary tract. We describe how a muscarinic agonist, arecaidine, influences intravesical pressure and intramural bladder contractions in the isolated mouse and how response varies in ageing mice. 2 A group of 12 mice aged 3-4 months was compared with an 'ageing' group of 12 mice age 28-34 months. Bladders were microsurgically removed and mounted in whole organ tissue baths. The effects of the muscarinic agonist arecaidine on intravesical pressure and intramural contractions were performed at different bladder volumes. 3 In normal mice, arecaidine elicited tonic and phasic contractions, the latter showing a more substantial increase in amplitude with bladder distension. Localized 'micromotion' contractions were seen in the bladder wall, with regional differences arising after exposure to arecaidine. A background release of acetylcholine was inferred from the pressure increase induced by the cholinesterase inhibitor physostigmine. 4 Both micromotion activity and the phasic component of the arecaidine response were substantially reduced in ageing mice; the tonic component was preserved in the same specimens. 5 We conclude that the enhanced pressure fluctuations seen at high bladder volumes may act as a peripheral determinant of bladder capacity, and that changes in such activity may contribute to altered functional capacity and lower urinary tract symptoms in ageing individuals.

Prospective evaluation of urological effects of aging in chronic spinal cord injury by method of bladder management.

AIMS: Risk of treatment-related problems in spinal cord injury (SCI) mandates assessment of complication rates of different bladder management methods (BMMs). The current study evaluated aging-related complications of various BMMs over a 6-year period in a population with spinal cord injury for at least 20 years. MATERIALS AND METHODS: Clinical parameters were compared using a linear mixed effects model, controlling for various confounding variables, to establish complication trends with aging and their association with BMM. Results for people whose BMM was changed during the study were evaluated separately as well as in combination with the whole population. RESULTS: One hundred and ninety six people (mean age 57.4 and years post injury (YPI) 33) were evaluated on three occasions. Both age and YPI were significantly associated with rising complication rates regardless of BMM. The BMMs assessed differed in terms of complication rates. In comparison with balanced reflex voiding, straining was significantly better for renal structural abnormality. Intermittent catheterization was associated with significantly worse renal function, possibly for demographic reasons. Overall, 28.8% changed BMM during the study period, particularly, those using straining or balanced reflex voiding. The probability of change increased with age and YPI. Reasons for change of BMM were varied and there was no specific association between reason for change and BMM. CONCLUSIONS: Aging and duration of injury substantially influence urological complication rates, and BMM options differ in respect of prevalence and incidence of complications. At a late stage post injury there remains a high probability of change in BMM. The findings indicate the importance of long-term planning from the time of injury to minimize late complications.

The actions of sodium nitroprusside and the phosphodiesterase inhibitor dipyridamole on phasic activity in the isolated guinea-pig bladder.

OBJECTIVE: To investigate the actions of the nitric oxide (NO) donor sodium nitroprusside (SNP) and phosphodiesterase (PDE) inhibitors, which purport to affect intracellular cGMP levels, on the phasic activity generated by agonist stimulation of the isolated whole bladder of the guinea pig. MATERIALS AND METHODS: Isolated whole bladders from female guinea pigs (270-300 g) were used in all experiments. Each bladder was cannulated via the urethra and suspended in a chamber containing oxygenated solution at 33-35 degrees C. Bladder pressure was recorded and pharmacological agents added to the solution bathing the abluminal surface of the bladder. RESULTS: In the unstimulated bladder, SNP at up to 300 micromol/L caused only small (<2 cmH(2)O) rises in intravesical pressure. In the presence of phasic activity induced by either muscarinic or nicotinic stimulation, SNP at > 30 micromol/L, produced a dose-dependent increase in the frequency of the transients. The cells responding to SNP with an increase in intracellular cGMP were identified by immunofluorescence, and were in the suburothelial layer and within the muscle bundles. Smooth muscle cells of the detrusor body did not show a rise in cGMP. Exposure to the cGMP/PDE inhibitor zaprinast had no effect on phasic activity, but exposure to dipyridamole produced a transient rise in frequency, followed by an inhibition. Dipyridamole also significantly increased the amplitude of the phasic activity. CONCLUSION: These data show an excitatory role for NO/cGMP in the integrated regulation of phasic bladder activity. One population of cells which may be involved may be in the suburothelial layer and within the muscles. The differential sensitivity to PDE inhibitors affecting cGMP suggests that the cells responsible express specific isoforms of these regulatory enzymes. The importance of these observations, their possible role in the integrated physiology of the bladder and origins of bladder pathology, are discussed.

Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement.

PURPOSE: Nocturia is a common condition often attributed in aging men to benign prostatic enlargement. Older adults are prone to nocturnal sleep disturbance, of which disturbed circadian rhythm may be a component since it improves with nighttime administration of melatonin. This study was designed to investigate melatonin as a potential treatment for nocturia associated with bladder outflow obstruction in older men. MATERIALS AND METHODS: A total of 20 men with urodynamically confirmed bladder outflow obstruction and nocturia were entered into a randomized, double blind, placebo controlled crossover study assessing the effect of 2 mg controlled release melatonin at night on nocturia. Symptoms were assessed at baseline and after each 4-week treatment period using a frequency volume chart, the International Prostate Symptom Score and symptom problem index. Maximum urinary flow rate and post-void residual urine volume were also assessed. RESULTS: Baseline frequency of nocturia was 3.1 episodes per night. There were 7 men (35%) with detrusor overactivity and 10 (50%) had nocturnal polyuria. Melatonin and placebo caused a decrease in nocturia of 0.32 and 0.05 episodes per night (p = 0.07) and a decrease in the nocturia bother score of 0.51 and 0.05, respectively (p = 0.008). Nocturia responder rates (a reduction from baseline of at least -0.5 episodes per night) differed between the active medication and placebo groups (p = 0.04). Daytime urinary frequency, International Prostate Symptom Score, relative nocturnal urine volume, maximum urinary flow rate and post-void residual were unaffected by melatonin treatment. CONCLUSIONS: Melatonin treatment is associated with a significant nocturia response rate, improvement in nocturia related bother and a good adverse effect profile. However, it is uncertain whether the observed changes in this study are clinically significant.

Innervation of the detrusor muscle bundle in neurogenic detrusor overactivity.

OBJECTIVE: To evaluate the peripheral anatomical distribution of innervation within muscle bundles of the detrusor and the changes arising in neurogenic detrusor overactivity (DO). PATIENTS AND METHODS: Full-thickness samples from the bladder dome of three cadaveric transplant organ donors and four people with neurogenic DO caused by spinal cord injury were compared. Systematic serial cryostat sections were stained using Masson trichrome and elastin techniques, and vimentin immunohistochemistry. A coherent image stack was generated for three-dimensional image reconstructions, which were displayed using mixed rendering (i.e. differing graphics for separate tissue components) to show peri- and intra-bundle innervation against the muscle fascicle framework. RESULTS: Control specimens had a dense nerve supply. Muscle bundle innervation was derived by dichotomous branching from peri-bundle nerve trunks in the inter-bundle connective tissue. Transverse interfascicular branches entered bundles perpendicular to the long axis at the midpoint of the bundle. They gave rise to axial interfascicular branches, which distributed to the pre-terminal and terminal nerve fibres. All samples from patients with neurogenic DO had patchy denervation. The primary deficit was predominantly at the level of the terminal axial innervation and was cross-sectionally consistent along the longitudinal axis of the muscle bundle. CONCLUSION: Patchy denervation may reflect a deficit at the level of the peripheral ganglia. Any contraction in the areas of denervation either occurs out of co-ordination with the rest of the bladder, or is co-ordinated by means of non-neural structures. The observation of fine muscle strands running between fascicles, and connective tissue anchoring structures, represent two hypothetical mechanisms by which such co-ordination might be effected.

Agonist- and nerve-induced phasic activity in the isolated whole bladder of the guinea pig: evidence for two types of bladder activity.

Spontaneous localised propagating waves of contraction and localised stretches have been reported to occur in the isolated whole bladder of the guinea pig. The physiological role and the cellular processes underlying these events are unknown. In order to gain insight into the mechanisms generating this complex activity, experiments were performed to examine and compare the responses of the whole bladder preparation to (i) the muscarinic agonists carbachol and arecaidine, (ii) the nicotinic ligand lobeline and (iii) nerve stimulation. High concentrations of the muscarinic agonists (>3 micro M) induced a slow rise in intra-vesical pressure upon which were superimposed pressure transients, while low concentrations (< 300 nM) induced only phasic rises in pressure. One interpretation of these data is that there are two separate mechanisms activated by muscarinic agonists: one generating contracture and the other phasic activity. Immunocytochemical staining revealed M(3) muscarinic receptors on smooth muscle cells within trabeculae and a second population of positive cells in the sub-urothelial layer. This observation raises the possibility that the actions of muscarinic agonists are a consequence of activating different cell types. Lobeline (1-60 micro M) activated phasic contractions but did not cause a rise in basal pressure. Atropine did not inhibit the lobeline-induced responses but abolished the muscarinic responses. Also, hexamethonium or tetrodotoxin did not affect the lobeline-induced responses. These observations suggest that the mechanism generating phasic activity is activated by a nicotinic stimulus that does not involve ganglia, nerves or the neuromuscular junction. Stimulation of the bladder nerve at frequencies between 20 and 30 Hz for 5 s resulted in a rapid rise in intra-vesical pressure. Prolonged nerve stimulation (10-200 s) at frequencies between 1 and 10 Hz activated phasic rises in pressure. Low frequency nerve stimulation increased the frequency of agonist-induced phasic activity. Thus, nerve stimulation can also produce two forms of activity and low frequency stimulation can augment the processes generating phasic activity. These observations suggest that there are two distinct types of bladder activity: global contractions involving most of the bladder wall and phasic contractions comprising propagating waves of contraction. The mechanisms generating these contractile events appear to be different and they may involve cells located in different regions of the bladder. The nature of these mechanisms and their possible physiological significance is discussed.