Autonomic dysfunction and plasticity in micturition reflexes in human α-synuclein mice.

Although often overshadowed by the motor dysfunction associated with Parkinson's disease (PD), autonomic dysfunction including urinary bladder and bowel dysfunctions are often associated with PD and may precede motoric changes; such autonomic dysfunction may permit early detection and intervention. Lower urinary tract symptoms are common in PD patients and result in significant morbidity. This studies focus on nonmotor symptoms in PD using a transgenic mouse model with overexpression of human α-synuclein (hSNCA), the peptide found in high concentrations in Lewy body neuronal inclusions, the histopathologic hallmark of PD. We examined changes in the physiological, molecular, chemical, and electrical properties of neuronal pathways controlling urinary bladder function in transgenic mice. The results of these studies reveal that autonomic dysfunction (i.e., urinary bladder) can precede motor dysfunction. In addition, mice with hSNCA overexpression in relevant neuronal populations is associated with alterations in expression of neurotransmitter/neuromodulatory molecules (PACAP, VIP, substance P, and neuronal NOS) within neuronal pathways regulating bladder function as well as with increased NGF expression in the urinary bladder. Changes in the electrical and synaptic properties of neurons in the major pelvic ganglia that provide postganglionic innervation to urogenital tissues were not changed as determined with intracellular recording. The urinary bladder dysfunction observed in transgenic mice likely reflects changes in peripheral (i.e., afferent) and/or central micturition pathways or changes in the urinary bladder. SYN-OE mice provide an opportunity to examine early events underlying the molecular and cellular plasticity of autonomic nervous system pathways underlying synucleinopathies.

Algorithms for the management of overactive bladder.

Overactive bladder (OAB) is a highly prevalent and bothersome condition that hampers quality of life in men and women. Increased awareness of available treatment has led growing numbers of patients to seek medical attention in search of relief. Clinical algorithms for the management of OAB would enable physicians who treat these patients to deliver up-to-date, effective care in an expeditious fashion. An algorithmic approach to OAB should allow most patients to receive therapy without the need for an extended evaluation. Patients who fail initial management or have more complicated clinical scenarios should have treatment directed by specialists who can precisely determine the nature of vesicourethral dysfunction underlying their symptoms. This article presents algorithms for the management of OAB in women, men, and patients with neurologic disease.

Preview of new drugs for overactive bladder and incontinence: darifenacin, solifenacin, trospium, and duloxetine.

This year, the US Food and Drug Administration will approve four new drugs indicated for the treatment of lower urinary tract dysfunction. Darifenacin, solifenacin, and trospium are antimuscarinic agents aimed at relieving the symptoms of overactive bladder and urge incontinence in men and women. Duloxetine will be the first drug approved for the treatment of female stress urinary incontinence. This article presents current data on the efficacy and tolerability of these new agents and invites the reader to decide whether they offer any potential advantages over existing therapies.

Functional brain imaging and the bladder: new insights into cerebral control over micturition.

Mechanisms for cerebral control over the micturition process remain poorly elucidated. The knowledge is based largely on human pathophysiology and data derived from electrophysiologic testing in animals. Recent advances in dynamic functional brain imaging technologies including positron-emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging have allowed new insights into how the human brain regulates this process. This article discusses animal studies, which provided the foundation for our understanding of cerebral control over micturition, and recent human studies, implementing functional brain imaging to enhance our knowledge of this complex phenomenon.

Beyond collagen: injectable therapies for the treatment of female stress urinary incontinence in the new millennium.

Previous experience with GAX-collagen has shown that the endoscopic correction of female SUI is both possible and effective. It is clear, however, that durability remains a primary concern when implementing this approach to treatment. The availability of recently developed and newly emerging materials, carefully designed using the tenets and techniques of biotechnology and materials science, may provide solutions to some of the difficulties beleaguering this treatment option. Results with currently available injectables are summarized in Table 1. Careful review and critical analysis of new bulking agents will soon reveal which materials approach the therapeutic ideal. It is likely that the ultimate choice of a particular substance, synthetic or biologic, may best be determined by the clinical circumstances involving the individual patient.

De novo urge syndrome and detrusor instability after anti-incontinence surgery: current concepts, evaluation, and treatment.

The onset of de novo irritative voiding symptoms after anti-incontinence surgery for stress urinary incontinence is troubling to both patient and physician alike. At present, mechanisms responsible for the development of these symptoms are incompletely elucidated. Although bladder outlet obstruction may certainly be a cause, correct diagnosis and treatment of this condition in its more insidious manifestation may be difficult. In addition, alternative etiologic factors related to surgical technique during outlet enhancing surgery may play a role, prompting a rethinking of these procedures. In this discussion, we review changes in voiding physiology and mechanisms for voiding dysfunction after anti-incontinence surgery, emphasizing de novo urge syndrome and detrusor instability. In addition, we present our approach to the evaluation, diagnosis, and treatment of these challenging patients.

Reconstitution of human corpus cavernosum smooth muscle in vitro and in vivo.

A large number of congenital and acquired abnormalities of the genitalia would benefit from the availability of transplantable, autologous corpus cavernosum tissue for use in reconstructive procedures. We describe the results of preliminary experiments designed to determine the feasibility of using cultured human corporal smooth muscle cells seeded onto biodegradable polymer scaffolds for the formation of corpus cavernosum smooth muscle in vitro and in vivo. Primary cultures of human corpus cavernosum smooth muscle cells were derived from operative biopsies obtained during penile prosthesis implantation. Cells were characterized in vitro and seeded as a contiguous multilayered sheet onto polymers of non-woven polyglycolic acid. The seeded polymer constructs were then implanted subcutaneously in athymic mice. Animals were killed 7, 14, and 24 days after surgery and implants were examined via histology, immunocytochemistry, and Western blot analyses. Cultured cell multilayers were identified as smooth muscle before implantation via phase-contrast microscopy, immunocytochemistry and Western blot analyses. Retrieved implants from all time points demonstrated corporal smooth muscle tissue grossly, and histologically, at the time of sacrifice. Intact smooth muscle cell multilayers were observed growing along the surface of the polymers. There was evidence of early vascular ingrowth at the periphery of the implants by 7 days. By 24 days, there was evidence of polymer degradation. Maintenance of the smooth muscle phenotype in vivo was confirmed immunocytochemically and by Western blot analyses with antibodies to alpha-smooth muscle actin. This study provides evidence that cultured human corporal smooth muscle cells may be used in conjunction with biodegradable polymer scaffolds to create corpus cavernosum smooth muscle tissue in vitro and in vivo.

Blood flow, pressure and compliance in the male human bladder.

PURPOSE: The regulation of human bladder blood flow during filling is poorly understood. We characterized changes in bladder blood flow with filling and examined the relationship of bladder compliance and blood flow. MATERIALS AND METHODS: A total of 17 awake male patients underwent saline cystometry followed by cystoscopy while under local anesthesia, during which a laser Doppler flow probe was placed into the posterior bladder wall detrusor. Systemic blood pressure, bladder blood flow and intravesical pressure were measured with the bladder empty and filled to 25%, 50%, 75% and 100% of awake maximum cystometric capacity as well as immediately after bladder drainage. RESULTS: Mean bladder blood flow was lowest in the empty bladder and increased with bladder filling. A mean peak flow plus or minus standard error of 7.6 +/- 1.1 ml. per minute per 100 gm. tissue was observed at volumes greater than 75% but less than 100% of maximum cystometric capacity. At 100% maximum cystometric capacity mean intravesical pressure increased by 73% from 25.2 to 43.5 cm. water and bladder blood flow decreased by 36%. Rapid bladder drainage was associated with a rebound in mean bladder blood flow to approximately 1.6 times baseline. Bladder compliance calculated for the whole filling curve positively correlated with bladder blood flow (p = 0.025), that is low compliance was associated with low blood flow. CONCLUSIONS: Human bladder blood flow tends to increase with increasing volume and pressure, and depends largely on local regulation. At capacity bladder blood flow is significantly decreased. Immediately after bladder drainage there is a rebound in blood flow, allowing reperfusion to occur. Decreased bladder blood flow and decreased bladder wall compliance correlated strongly, suggesting that ischemia may lead to structural changes in the bladder wall.