Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials.

AIMS: Two phase 1 trials were performed in healthy women with the overactive bladder (OAB) syndrome and urodynamically demonstrated detrusor overactivity (DO), with the aim to demonstrate the safety and potential efficacy of URO-902, which comprises a gene therapy plasmid vector expressing the human big potassium channel α subunit. METHODS: ION-02 (intravesical instillation) and ION-03 (direct injection) were double-blind, placebo-controlled, multicenter studies without overlap in enrollment between studies. Active doses were administered and evaluated sequentially (lowest dose first) for safety. ION-02 participants received either 5000 µg or 10 000 µg URO-902, or placebo. ION-03 participants received either 16 000 or 24 000 µg URO-902, or placebo, injected directly into the bladder wall using cystoscopy. Primary outcome variables were safety parameters occurring subsequent to URO-902 administration; secondary efficacy variables also were evaluated. RESULTS: Among the safety outcomes, there were no dose-limiting toxicities or significant adverse events (AEs) preventing dose escalation during either trial, and no participants withdrew due to AEs. For efficacy, in ION-02 (N = 21), involuntary detrusor contractions on urodynamics at 24 weeks in patients receiving URO-902 (P < .0508 vs placebo) and mean urgency incontinence episodes in the 5000 µg group (P = .0812 vs placebo) each showed a downward trend. In ION-03 (N = 13), significant reduction versus placebo in urgency episodes (16 000 µg, P = .036; 24 000 µg, P = .046) and number of voids (16 000 µg, -2.16, P = .044; 24 000 µg, -2.73, P = .047) were observed 1 week after injection. CONCLUSION: Promising safety and efficacy results in these preliminary phase 1 studies suggest gene transfer may be a promising therapy for OAB/DO, warranting further investigation.

The Effects of a Genital Vibratory Stimulation Device on Sexual Function and Genital Sensation.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of a genital vibratory stimulation device in improving sexual function in women with arousal and orgasm disorders. METHODS: In this single-arm, prospective study, baseline and 1- and 3-month assessments were performed to evaluate women with sexual arousal and/or orgasmic disorders, who received therapy using a genital vibratory stimulation device. Sexual function, satisfaction, and distress were evaluated using the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale, and the Female Intervention Efficacy Index questionnaires. Genital sensation was evaluated using quantitative sensory testing. RESULTS: Seventy women, aged 19 to 64 years, were evaluated from October 2009 to August 2013. Forty-seven (67.1%) and 37 (52.9%) women completed 1- and 3-month follow-ups, respectively. The FSFI arousal and orgasm domain scores and total FSFI scores improved at 1 and 3 months (P < 0.001 for all outcomes). Mean (SD) total FSFI scores increased from 20.04 (4.65) (baseline) to 25.03 (5.21) (1 month) to 26.66 (5.42) (3 months; both Ps < 0.0001). Female Sexual Distress Scale scores reflected significantly decreased distress at 1 (P = 0.0006) and 3 (P < 0.0001) months compared with baseline and at 3 months compared with 1 month (P = 0.03). Neurological sensation was increased at all genital sites at 1 and 3 months (P < 0.0001 for all). After adjustment for age, there was a significant interaction between arousal domain scores and clitoral and right labial sensation. At 3 months, perceptions of increased vaginal lubrication, orgasm, and genital sensation were reported by 67.5%, 65.0%, and 82.5% of the participants. No major adverse events were noted. CONCLUSIONS: Genital vibratory stimulation device use resulted in uniform improvements in sexual function, satisfaction, sexually related distress and genital sensation.

Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells.

Men with sickle cell disease (SCD) risk developing priapism. Recognizing that SCD is a disease of hypoxia, we investigated the effect of hypoxia on gene expression in corporal smooth muscle (CSM) cells. Rat CSM cells in vitro were treated with CoCl2 or low oxygen tension to mimic hypoxia. Hypoxic conditions increased expression of genes previously associated with priapism in animal models. Variable coding sequence a1 (Vcsa1; the rat opiorphin homologue, sialorphin), hypoxia-inducible factor 1a (Hif-1a), and A2B adenosine receptor (a2br) were increased by 10-, 4-, and 6-fold, respectively, by treatment with CoCl2, whereas low oxygen tension caused increases in expression of 3-, 4-, and 1.5-fold, respectively. Sialorphin-treated CSM cells increased expression of Hif-1a and a2br by 4-fold, and vcsa1-siRNA treatment reduced expression by ∼50%. Using a Hif-1a inhibitor, we demonstrated up-regulation of a2br by sialorphin is dependent on Hif-1a, and knockdown of vcsa1 expression with vcsa1-siRNA demonstrated that hypoxic-up-regulation of Hif-1a is dependent on vcsa1. In CSM from a SCD mouse, there was 15-fold up-regulation of opiorphin at a life stage prior to priapism. We conclude that in CSM, opiorphins are master regulators of the hypoxic response. Opiorphin up-regulation in response to SCD-associated hypoxia activates CSM "relaxant" pathways; excessive activation of these pathways results in priapism.

Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity.

OBJECTIVES: To investigate the effect of diabetes on urothelial modulation of bladder contractility. METHODS: Bladder strips (urothelium intact or denuded) were prepared from 8-week-old streptozotocin-induced diabetic (n = 19) and non-diabetic control rats (n = 10). The effect of modulators of MaxiK (iberiotoxin and tetraethylammonium) and Kv7 (XE991 and retigabine) potassium channel activity were investigated for their effects on both carbachol-induced force generation and spontaneous contractile activity. RESULTS: In bladder strips from non-diabetic animals, the presence of the urothelium resulted in marked sensitivity to carbachol-induced force generation by modulators of MaxiK and Kv7 channel activity, whereas in the diabetic animal urothelial sensitivity to these agents was significantly diminished. Urothelial-intact bladder strips from non-diabetic animals were more sensitive to modulators of Kv7 activity in reducing the amplitude of spontaneous phasic contractions than urothelial-denuded bladder strips, whereas in diabetic animals the presence or absence of the urothelium did not alter the sensitivity to modulators of Kv7 activity. Spontaneous activity in the presence of tetraethylammonium was not affected by the urothelium in bladder strips from either diabetic or non-diabetic animals. CONCLUSIONS: The presence of the urothelium in bladders from non-diabetic animals modulates the activity of potassium blockers to affect bladder contractility, whereas in the diabetic bladder this effect is attenuated. These findings could help to explain the lack of success of pharmaceutical treatments targeting potassium channels to treat bladder pathology in patients with diseases imparing urothelial function.

Large-conductance calcium-activated potassium channel activity, as determined by whole-cell patch clamp recording, is decreased in urinary bladder smooth muscle cells from male rats with partial urethral obstruction.

OBJECTIVES: To examine the effect of partial urethral obstruction (PUO) on bladder smooth muscle outward potassium current and the contribution of the large-conductance calcium-activated potassium (Maxi-K, BKCa) channel to this activity in smooth muscle cells isolated from bladders of sham-operated and PUO male rats using whole-cell patch clamp recording techniques. To determine the effect of PUO on the expression of the Maxi-K channel α and ß1 subunits and in vitro detrusor contractility. MATERIALS AND METHODS: Twenty adult male Sprague-Dawley rats were divided equally into two groups and subjected to surgical ligation of the urethra (PUO) or sham surgery (SHAM). After 2 weeks, the detrusors from PUO and SHAM rats were used for molecular analyses (mRNA and protein quantification of Maxi-K subunits) or organ bath contractility studies, or myocytes were isolated for conventional whole-cell patch clamp analyses. RESULTS: PUO increased bladder mass 2.5-fold and detrusor strips exhibited a more tonic-type contraction and increased contractility compared with controls (SHAM). Iberiotoxin (300 nM) sensitive Maxi-K channel current comprised about 40% of the outward whole-cell current in SHAM bladders but only about 8% in PUO bladders. Expression of the α subunit of the Maxi-K channel was significantly decreased ~40% while the expression of the ß1 subunit was increased ~2-fold at the mRNA level. The increase in ß1 expression was confirmed by Western blotting. CONCLUSIONS: Our findings show that obstruction of the rat bladder is associated with decreased Maxi-K channel activity of bladder smooth muscle cells, determined via direct current measurement. Increased expression of the ß1 subunit points to a compensatory reaction to decreased Maxi-K channel activity. Maxi-K channel openers or gene therapy may therefore provide therapeutic benefit for the overactive bladder.

Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways.

OBJECTIVE: • To investigate the role that oxidative stress plays in the development of diabetic cystopathy. MATERIALS AND METHODS: • Comparative gene expression in the bladder of non-diabetic and streptozotocin (STZ)-induced 2-month- old diabetic rats was carried out using microarray analysis. • Evidence of oxidative stress was investigated in the bladder by analyzing glutathione S-transferase activity, lipid peroxidation, and carbonylation and nitrosylation of proteins. • The activity of protein degradation pathways was assessed using Western blot analysis. RESULTS: • Analysis of global gene expression showed that detrusor smooth muscle tissue of STZ-induced diabetes undergoes significant enrichment in targets involved in the production or regulation of reactive oxygen species (P = 1.27 × 10(-10)). The microarray analysis was confirmed by showing that markers of oxidative stress were all significantly increased in the diabetic bladder. • It was hypothesized that the sequelae to oxidative stress would be increased protein damage and apoptosis. • This was confirmed by showing that two key proteins involved in protein degradation (Nedd4 and LC3B) were greatly up-regulated in diabetic bladders compared to controls by 12.2 ± 0.76 and 4.4 ± 1.0-fold, respectively, and the apoptosis inducing protein, BAX, was up-regulated by 6.76 ± 0.76-fold. CONCLUSION: • Overall, the findings obtained in the present study add to the growing body of evidence showing that diabetic cystopathy is associated with oxidative damage of smooth muscle cells, and results in protein damage and activation of apoptotic pathways that may contribute to a deterioration in bladder function.

In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin.

OBJECTIVE To investigate the in vitro and in vivo effects of blebbistatin (a small cell-permeable molecule with high affinity and selectivity toward the myosin II contractile molecule) on bladder smooth muscle (SM) contractility, as antimuscarinic therapy is only 65-75% effective in treating overactive bladder (OAB) and is associated with considerable side-effects, with a < 25% continuation rate at 1 year. MATERIALS AND METHODS Bladder and aortic strips from adult male rats, and human bladder strips obtained from open prostatectomy, were used for organ-bath studies of blebbistatin. Awake cystometry was also used in rats in both the presence and absence of intravesically delivered blebbistatin. RESULTS Blebbistatin dose-dependently and completely relaxed both KCl- and carbachol-induced rat detrusor and endothelin-1-induced human bladder contraction. Pre-incubation with 10 µm blebbistatin attenuated carbachol responsiveness by ≈ 65% while blocking electrical field stimulation-induced bladder contraction reaching 50% inhibition at 32 Hz. The basal tone and amplitude of spontaneous contraction were also significantly diminished. Urodynamic variables were obviously altered by intravesical infusion with blebbistatin. CONCLUSION Our novel data show that blebbistatin strongly relaxes both rat and human bladder contraction induced by various physiological stimuli. Coupled with our in vivo data showing that nanomole doses of blebbistatin significantly alter urodynamic variables to produce a less active bladder, our results suggest the possibility of intravesically administered blebbistatin binding at myosin II being developed as a therapeutic treatment for OAB via a novel targeting of the SM contractile apparatus.

Impact of hormones on female sexual function and dysfunction.

The female sexual response cycle is a complex system composed of physiologic changes, psychological, and cultural factors. Female sexual dysfunction (FSD) encompasses a variety of sexual problems, including low desire or interest, diminished arousal, difficulties with orgasm, and dyspareunia. Research in female sexual function and dysfunction has lagged significantly behind males despite our current knowledge that FSD can occur in as many of 80% of the female population. Basic science research exists but also identifies serious gaps in our fundamental knowledge of this area. The purpose of this article was to review our current understanding of the effects of hormones on normal physiologic sexual responses in women, female sexual function and dysfunction, and the available treatment options for the various components of FSD.

Standards for clinical trials in male sexual dysfunctions.

INTRODUCTION: Clinical trials in male sexual dysfunction (MSD) are expanding. Consequently, there is a need for consensus standards in this area. AIM: To develop an evidence-based, state-of-the-art consensus report on standards for clinical trials in MSD. METHODS: A literature review was performed examining clinical trials in erectile dysfunction (ED), premature ejaculation (PE), delayed/absent ejaculation, libido disorders/loss of desire, hypogonadism, and Peyronie's disease, focusing on publications published in the last 20 years. This manuscript represents the opinions of eight experts from seven countries developed in a consensus process. This document was presented for peer review and debate in a public forum and revisions were made based on recommendations of chairpersons to the International Consultation on Sexual Medicine. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: According to experience and recent publications in dealing with clinical trials in sexual dysfunction, recommendations have been made for conducting trials in patients with ED, PE, delayed ejaculation, libido disorders, hypogonadism, and Peyronie's disease. CONCLUSIONS: It is important that future clinical trials are conducted using standards upon which investigators can rely when reading manuscripts or conducting new trials in this field.

The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway.

Intracorporal injection of plasmids encoding opiorphins into retired breeder rats can result in animals developing a priapic-like condition. Microarray analysis demonstrated that following intracorporal gene transfer of plasmids expressing opiorphins the most significantly upregulated gene in corporal tissue was the ornithine decarboxylase gene (ODC). Quantitative RT-PCR confirmed the upregulation of ODC, as well as other genes involved in polyamine synthesis, such as arginase-I and -II, polyamine oxidase, spermidine synthase, spermidine acetyltransferase (SAT), and S-adenosylmethionine decarboxylase. Western blot analysis demonstrated upregulation of arginase-I and -II, ODC, and SAT at the protein level. Levels of the polyamine putrescine were upregulated in animals treated with opiorphin-expressing plasmids compared with controls. A direct role for the upregulation of polyamine synthesis in the development of the priapic-like condition was supported by the observation that the ODC inhibitor 1,3-diaminopropane, when added to the drinking water of animals treated with plasmids expressing opiorphins, prevented experimental priapism. We also demonstrate that in sickle cell mice, another model of priapism, there is increased expression of the mouse opiorphin homologue in corporal tissue compared with the background strain at a life stage prior to evidence of priapism. At a life stage when there is onset of priapism, there is increased expression of the enzymes involved in polyamine synthesis (ODC and arginase-I and -II). Our results suggest that the upregulation of enzymes involved in the polyamine synthetic pathway may play a role in the development of experimental priapism and represent a target for the prevention of priapism.

Alterations in bladder function associated with urothelial defects in uroplakin II and IIIa knockout mice.

AIMS: The effects of deleting genes encoding uroplakins II (UPII) and III (UPIIIa) on mouse bladder physiology/dysfunction were studied in male and female wild type and knockout (KO) mice. METHODS: UPII, UPIIIa, and WT mice were catheterized using previously described techniques. Continuous cystometry was conducted in conscious, freely moving animals. Bladder strips were harvested after animal sacrifice and pharmacological studies and EFS were conducted in an organ chamber. Histological studies were also carried on with H&E staining to identify differences among the three mouse types. RESULTS: These studies have revealed numerous alterations, some of which were apparently gender-specific. Nonvoiding contractions were common in both UPII and UPIIIa KO mice, although more severe in the former. In particular, the increased bladder capacity, micturition pressure and demonstrable nonvoiding contractions observed in the male UPII KO's, were reminiscent of an obstruction-like syndrome accompanied by evidence of emerging bladder decompensation, as reflected by an increased residual volume. Pharmacological studies revealed a modest, gender-specific reduction in sensitivity of isolated detrusor strips from UPII KO female mice to carbachol-induced contractions. A similar reduction was observed in UPIIIa KO female mice. Histological investigation showed urothelial hyperplasia in both UPII KO and UPIIIa KO mice, although again, apparently more severe in the former. CONCLUSIONS: These results confirm and extend previous work to indicate that urothelial defects due to uroplakin deficiency are associated with significant alterations in bladder function and further highlight the importance of the urothelium to bladder physiology/dysfunction.

Effects of ageing and streptozotocin-induced diabetes on connexin43 and P2 purinoceptor expression in the rat corpora cavernosa and urinary bladder.

OBJECTIVE: To investigate whether ageing and diabetes alter the expression of the gap junction protein connexin43 (Cx43) and of particular purinoceptor (P2R) subtypes in the corpus cavernosum and urinary bladder, and determine whether changes in expression of these proteins correlate with development of erectile and bladder dysfunction in diabetic and ageing rats. MATERIALS AND METHODS: Erectile and bladder function of streptozotocin (STZ)-induced diabetic, insulin-treated and age-matched control Fischer-344 rats were evaluated 2, 4 and 8 months after diabetes induction by in vivo cystometry and cavernosometry. Corporal and bladder tissue were then isolated at each of these sample times and protein expression levels of Cx43 and of various P2R subtypes were determined by Western blotting. RESULTS: In the corpora of control rats ageing was accompanied by a significant decrease in Cx43 and P2X(1)R, and increase in P2X(7)R expression. There was decreased Cx43 and increased P2Y(4)R expression in the ageing control rat bladder. There was a significant negative correlation between erectile capacity and P2X(1)R expression levels, and a positive correlation between bladder spontaneous activity and P2Y(4)R expression levels. There was already development of erectile dysfunction and bladder overactivity at 2 months after inducing diabetes, the earliest sample measured in the study. The development of these urogenital complications was accompanied by significant decreases in Cx43, P2Y(2)R, P2X(4)R and increase in P2X(1)R expression in the corpora, and by a doubling in Cx43 and P2Y(2)R, and significant increase in P2Y(4)R expression in the bladder. Changes in Cx43 and P2R expression were largely prevented by insulin therapy. CONCLUSION: Ageing and diabetes mellitus markedly altered the expression of the gap junction protein Cx43 and of particular P2R subtypes in the rat penile corpora and urinary bladder. These changes in Cx43 and P2R expression provide the molecular substrate for altered gap junction and purinergic signalling in these tissues, and thus probably contribute to the early development of erectile dysfunction and higher detrusor activity in ageing and in diabetic rats.

Transcription of G-protein coupled receptors in corporeal smooth muscle is regulated by the endogenous neutral endopeptidase inhibitor sialorphin.

PURPOSE: Several reports suggest that the rat Vcsa1 gene is down-regulated in models of erectile dysfunction. The Vcsa protein product sialorphin is an endogenous neutral endopeptidase inhibitor and its down-regulation could result in prolonged activation of G-protein activated signaling pathways by their peptide agonists. We investigated whether Vcsa1 down-regulation could result in an adaptive change in GPCR (G-protein coupled receptor) expression. MATERIALS AND METHODS: Gene expression in cultured rat corporeal smooth muscle cells following treatment with siRNA directed against Vcsa1 or the neutral endopeptidase gene was analyzed using microarray and quantitative reverse transcriptase-polymerase chain reaction. In rats Vcsa1 is one of the most down-regulated genes following bilateral transection of the cavernous nerves. In that animal model we also investigated whether Vcsa1 down-regulation was accompanied by similar changes in gene expression in corporeal smooth muscle cells in which Vcsa1 was knocked down in vitro. RESULTS: Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction demonstrated that corporeal smooth muscle cells treated in vitro with siRNA against Vcsa1 resulted in GPCR up-regulation as a functional group. In contrast, treatment of corporeal smooth muscle cells that lowered neutral endopeptidase activity resulted in decreased GPCR expression. These results suggest that the peptide product of Vcsa1, sialorphin, can effect GPCR expression by acting on neutral endopeptidase. In animals with bilaterally transected cavernous nerves the decreased Vcsa1 expression is accompanied by increased GPCR expression in cavernous tissue. CONCLUSIONS: These experiments suggest that the mechanism by which Vcsa1 modulates erectile function is partly mediated through changes in GPCR expression.

Comparison of open and laparoscopic nephrectomy in obese and nonobese patients: outcomes stratified by body mass index.

PURPOSE: Laparoscopic radical nephrectomy has been accepted as the preferred management for low stage renal masses not amenable to partial nephrectomy. Early in the mid 1990s several studies suggested that obesity should be a relative contraindication to laparoscopy. We present our surgical outcomes and complications in patients undergoing open and laparoscopic nephrectomy, stratified by body mass index. MATERIALS AND METHODS: We retrospectively identified 88 patients, of whom 43 underwent open nephrectomy and 45 were treated laparoscopically. All patients were stratified by body mass index to compare multiple perioperative end points and pathological outcomes of laparoscopy. RESULTS: Overall our data showed that compared to open nephrectomy laparoscopic nephrectomy resulted in statistically significant lower estimated blood loss (147.95 vs 640.48 cc, p <0.0002), operative time (156.11 vs 198.95 minutes, p <0.003) and hospital stay (3.7 vs 5.9 days, p <0.004). When stratified by body mass index less than 25, 25 to 29.9 and 30 kg/m(2) or greater, there was a statistically significant difference in estimated blood loss and hospital stay that was in favor of the laparoscopic approach in each body mass index category. Operative time did not show a statistical difference in the subgroups but all laparoscopic procedure times were shorter than open procedure times in each body mass index category. When patients with a body mass index of greater than 30 kg/m(2) were further subgrouped into 35 kg/m(2) or greater and 40 kg/m(2) or greater, there was a statistically significant difference in estimated blood loss and hospital stay that was again in favor of the laparoscopic method. CONCLUSIONS: Laparoscopic radical nephrectomy is technically more challenging as body mass index increases due to many factors but our data show that it is feasible and safe in experienced hands. Laparoscopy appears to result in perioperative outcomes that are superior to those of open nephrectomy in this high risk population with a complication profile that is equivalent to that of the open method for each stratified body mass index category.

hSMR3A as a marker for patients with erectile dysfunction.

PURPOSE: We recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in 3 distinct models of erectile dysfunction. Since gene transfer of plasmids expressing Vcsa1 or intracorporeal injection of its mature peptide product sialorphin into the corpora of aging rats was shown to restore erectile function, we proposed that the Vcsa1 gene has a direct role in erectile function. To determine if similar changes in gene expression occur in the corpora of human subjects with erectile dysfunction we identified a human homologue of Vcsa1 (hSMR3A) and determined the level of expression of hSMR3A in patients. MATERIALS AND METHODS: hSMR3A was identified as a homologue of Vcsa1 by searching protein databases for proteins with similarity. hSMR3A cDNA was generated and subcloned into the plasmid pVAX to generate pVAX-hSMR3A. pVAX-hSMR3A (25 or 100 microg) was intracorporeally injected into aging rats. The effect on erectile physiology was compared histologically and by measuring intracorporeal pressure/blood pressure with controls treated with the empty plasmid pVAX. Total RNA was extracted from human corporeal tissue obtained from patients undergoing previously scheduled penile surgery. Patients were grouped according to normal erectile function (3), erectile dysfunction and diabetes (5) and patients without diabetes but with erectile dysfunction (5). Quantitative reverse-transcriptase polymerase chain reaction was used to determine the hSMR3A expression level. RESULTS: Intracorporeal injection of 25 microg pVAX-hSMR3A was able to significantly increase the intracorporeal pressure-to-blood pressure ratio in aging rats compared to age matched controls. Higher amounts (100 microg) of gene transfer of the plasmid caused less of an improvement in the intracorporeal pressure-to-blood pressure ratio compared to controls, although there was histological and visual evidence that the animals were post-priapitic. These physiological effects were similar to previously reported effects of intracorporeal injection of pVAX-Vcsa1 into the corpora of aging rats, establishing hSMR3A as a functional homologue of Vcsa1. More than 10-fold down-regulation in hSMR3A transcript expression was observed in the corpora of patients with vs without erectile dysfunction. In patients with diabetes associated and nondiabetes associated erectile dysfunction hSMR3A expression was found to be down-regulated. CONCLUSIONS: These results suggest that hSMR3A can act as a marker for erectile dysfunction associated with diabetic and nondiabetic etiologies. Given that our previous studies demonstrated that gene transfer of the Vcsa1 gene and intracorporeal injection of its protein product in rats can restore erectile function, these results suggest that therapies that increase the hSMR3A gene and product expression could potentially have a positive impact on erectile function.

Comparison of operative and functional outcomes of laparoscopic radical prostatectomy and radical retropubic prostatectomy: single surgeon experience.

OBJECTIVES: To compare radical retropubic prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP) outcomes in a contemporary series. METHODS: A total of 70 LRP patients operated on between 2001 and 2002 with at least 18 months of follow-up were selected. These patients were compared with a matched cohort of 70 patients who had undergone RRP by the same surgeon from 1999 to 2001. The baseline patient characteristics, perioperative and histologic parameters, recovery time, complications, and 18-month functional data were compared. RESULTS: No significant differences were found in the preoperative characteristics. The mean operative time was 181.8 +/- 18.7 minutes for RRP and 246.4 +/- 46.1 minutes for LRP (P <0.0001). The mean estimated blood loss was 563.2 mL for RRP and 275.8 mL for LRP (P <0.0001). The positive margin rate was 20% and 15.7% for the RRP and LRP groups, respectively (P = NS). The mean pain score on postoperative day 1 was 4.5 in the LRP group and 7.8 in the RRP group on an analog pain score of 0 to 10 (P = 0.02). Full recovery was achieved at 33 +/- 17 days and 45 +/- 20 days for the LRP and RRP groups, respectively (P <0.001). The total perioperative complication rate for LRP and RRP was comparable at 18.5% and 15.7%, respectively. The diurnal continence rate (no pads) for the LRP and RRP groups was 70%, 90%, and 92.8% and 71.4%, 87.6%, and 92% at 6, 12, and 18 months, respectively (P = NS). The potency rate after bilateral neurovascular preservation with or without sildenafil for the LRP and RRP group was 55%, 72.6%, and 79.5% and 43%, 58%, and 72.4% at 6, 12, and 18 months, respectively (P = NS). CONCLUSIONS: LRP is well tolerated and provides short-term oncologic and functional results comparable to those of RRP.

Effects of streptozotocin-induced diabetes on bladder and erectile (dys)function in the same rat in vivo.

OBJECTIVE: To establish the methods, feasibility and utility of evaluating the impact of diabetes on bladder and erectile function in the same rat, as more than half of diabetic patients have bladder dysfunction, and half of diabetic men have erectile dysfunction, but the severity of coincident disease has not been rigorously assessed. MATERIALS AND METHODS: In all, 16 F-344 rats had diabetes induced by streptozotocin (STZ), and were divided into insulin-treated (five) and untreated (11), and compared with age-matched controls (10), all assessed in parallel. All STZ rats were diabetic for 8-11 weeks. Cystometric studies were conducted on all rats, with cavernosometric studies conducted on a subset of rats. RESULTS: There were insulin-reversible increases in the following cystometric variables; bladder weight, bladder capacity, micturition volume, residual volume, micturition pressure and spontaneous activity (P < 0.05, in all, one-way analysis of variance, anova). Cavernosometry showed a diabetes-related, insulin-reversible decline in the cavernosal nerve-stimulated intracavernosal pressure (ICP) response at all levels of current stimulation (P < 0.05, in all one-way anova). Plotting erectile capacity (i.e. ICP) against bladder capacity showed no correlation between the extent of the decline in erectile capacity and the magnitude of the increase in bladder capacity. CONCLUSIONS: These studies extend previous work to indicate that the extent of diabetes-related bladder and erectile dysfunction can vary in the same rat. As such, these findings highlight the importance of evaluating the impact of diabetes on multiple organ systems in the lower urinary tract. Future studies using this model system should lead to a better understanding of the initiation, development, progression and coincidence of these common diabetic complications.

Trypanosoma cruzi infection induced changes in the innervation, structure and function of the murine bladder.

PURPOSE: The involvement of the lower urinary tract in chronic Chagas' disease has received little attention. Therefore, we investigated pathology and functional alterations in the bladder of Trypanosoma cruzi infected mice. MATERIALS AND METHODS: CD1 mice were infected with 5 x 10 T. cruzi trypomastigotes of the Brazil strain of T. cruzi. At day 100 after infection bladder structure and function were examined by pathological evaluation, magnetic resonance imaging and cystometric studies. RESULTS: The bladder in infected mice weighed more and were large, dilated, deformed, friable and thin walled compared with control mice. Magnetic resonance imaging confirmed these observations. Inflammation, fibrosis and ganglionitis was observed. Cystometric studies revealed that baseline, threshold and micturition pressures were increased in infected mice. Bladder overactivity and decreased bladder compliance were also noted in infected mice. There were no detectable differences in bladder capacity, micturition volume or residual volume between infected and uninfected mice. CONCLUSIONS: Bladder abnormalities may be a more common clinical sequelae of T. cruzi infection than previously appreciated.

Surgery for localized prostate cancer after renal transplantation.

OBJECTIVE: To investigate the feasibility of perineal radical prostatectomy (RP) in renal transplant recipients with localized prostate cancer. PATIENTS AND METHODS: The study comprised seven consecutive renal transplant patients who had a perineal RP between May 1991 and February 2004. All available clinicopathological data were reviewed. Results All seven patients successfully tolerated RP with no major complications. The mean (sd, range) age at surgery was 62.3 (2.5, 55-74) years and the mean interval from renal transplant to RP 86.5 (25.25, 24-192) months. There was no evidence of increased blood loss, operative duration, transfusion requirement, hospital stay or deterioration of graft function. The presence of an allograft did not alter the surgical approach or management of the patients after RP. The mean follow-up was 22 (2-130) months and all seven patients were followed. One patient had evidence of biochemical recurrence with no radiographic evidence of metastatic disease. Serum prostate-specific antigen was undetectable in the remaining patients. CONCLUSION: A perineal RP in renal transplant recipients for treating localized prostate cancer offers many advantages over other treatments.