Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress.

INTRODUCTION: The etiology of radiation-induced erectile dysfunction (ED) is complex and multifactorial, and it appears to be mainly atherogenic. AIM: To focus on vascular aspects of radiation-induced ED and to elucidate whether the protective effects of sildenafil are mediated by attenuation of oxidative stress and apoptosis in the endothelial cells. METHODS: Bovine aortic endothelial cells (BAECs), with or without pretreatment of sildenafil (5 µM at 5 minutes before radiation), were used to test endothelial dysfunction in response to external beam radiation at 10-15 Gy. Generation of reactive oxygen species (ROS) was studied. Extracellular hydrogen peroxide (H2O2) was measured using the Amplex Red assay and intracellular H2O2 using a fluorescent sensor. In addition, ROS superoxide (O2•-) was measured using a O2•- chemiluminescence enhancer. Both H2O2 and O2•- are known to reduce the bioavailability of nitric oxide, which is the most significant chemical mediator of penile erection. Generation of cellular peroxynitrite (ONOO-) was measured using a chemiluminescence assay with the PNCL probe. Subsequently, we measured the activation of acid sphingomyelinase (ASMase) enzyme by radioenzymatic assay using [14C-methylcholine] sphingomyelin as substrate, and the generation of the proapoptotic C16-ceramide was assessed using the diacylglycerol kinase assay. Endothelial cells apoptosis was measured as a readout of these cells' dysfunction. MAIN OUTCOME MEASURES: Single high-dose radiation therapy induced NADPH oxidases (NOXs) activation and ROS generation via the proapoptotic ASMase/ceramide pathway. The radio-protective effect of sildenafil on BAECs was due to inhibition of this pathway. RESULTS: Here, we demonstrate for the first time that radiation activated NOXs and induced generation of ROS in BAECs. In addition, we showed that sildenafil significantly reduced radiation-induced O2•- and as a result there was reduction in the generation of peroxynitrite in these cells. Subsequently, sildenafil protected the endothelial cells from radiation therapy-induced apoptosis. STRENGTHS AND LIMITATIONS: This is the first study demonstrating that single high-dose radiation therapy induced NOXs activation, resulting in the generation of O2•- and peroxynitrite in endothelial cells. Sildenafil reduced ROS generation by inhibiting the ASMase/ceramide pathway. These studies should be followed in an animal model of ED. CONCLUSIONS: This study demonstrated that sildenafil protects BAECs from radiation-induced oxidative stress by reducing NOX-induced ROS generation, thus resulting in decreased endothelial dysfunction. Therefore, it provides a potential mechanism to better understand the atherogenic etiology of postradiation ED. Wortel RC, Mizrachi A, Li H, et al. Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress. J Sex Med 2019;16:1721-1733.

Impact of cardiovascular risk factors and related comorbid conditions and medical therapy reported at baseline on the treatment response to tadalafil 5 mg once-daily in men with lower urinary tract symptoms associated with benign prostatic hyperplasia: an integrated analysis of four randomised, double-blind, placebo-controlled, clinical trials.

PURPOSE: The influence of cardiovascular risk factors/comorbidities on response to oral once-daily tadalafil 5 mg was explored in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). METHODS: This post hoc analysis pooled data from four double-blind studies in which 1498 men with > 6-mo history of LUTS/BPH were randomised and received either once-daily placebo (n = 746) or tadalafil 5 mg (n = 752) for 12 weeks. Descriptive statistics were reported for changes in total International Prostate Symptom Score (IPSS), IPSS voiding and storage subscores, and IPSS quality-of-life (QoL) index. Treatment group differences by baseline clinical and cardiovascular factors and medical therapies were examined using analysis of covariance. RESULTS: Tadalafil was effective in men with LUTS/BPH and cardiovascular risk factors/comorbidities except for patients receiving > 1 antihypertensive medication. Placebo-adjusted least squares (LS) mean improvements in total IPSS were -1.2 (95% CI: -2.5 to -0.0) in men taking > 1 antihypertensive medication vs. -3.3 (95% CI: -4.4 to -2.1) in men taking one medication (interaction p = 0.020). In addition, placebo-adjusted LS mean improvements in total IPSS were -0.2 (95% CI, -2.1 to 1.7) in men who reported use of diuretics vs. -2.8 (95% CI, -3.7 to -1.9) in men who reported taking other antihypertensive medications vs. -2.3 (95% CI, -3.2 to -1.5) in men who reported not using any antihypertensive drug (p-value for interaction = 0.053). CONCLUSIONS: Once-daily tadalafil 5 mg improved LUTS/BPH, regardless of severity, in men with coexisting cardiovascular risk factors/comorbidities, except for patients with history of > 1 drug for arterial hypertension. Use of diuretics may contribute to patients' perception of a negated efficacy of tadalafil on LUTS/BPH. Comorbidities should be considered when choosing the optimal medicine to treat men with LUTS/BPH.

Ciprofloxacin-induced acute psychosis.

Ciprofloxacin, one of the fluoroquinolone antibiotics, has become one of the most widely prescribed antimicrobial agents. It is generally well tolerated with a low incidence of side effects, which are mild in nature. There is a distinct incidence of neuropsychiatric adverse effects, which include psychotic reactions. We describe a case of a woman who experienced an acute psychosis secondary to ciprofloxacin administration, which resolved on cessation of therapy. All urologists should be aware of this problem and be familiar with the recommendations for ciprofloxacin use in patients with underlying neuropsychiatric problems.

Simultaneous microsurgical vasal reconstruction and varicocele ligation: safety profile and outcomes.

OBJECTIVES: Simultaneous varicocele ligation and vasal reconstruction has previously been avoided because of concern regarding testicular devascularization. This study sought to investigate the safety of a simultaneous combined approach in the hands of an experienced microsurgeon. METHODS: A retrospective review was conducted of the records of 47 men who underwent vasal reconstruction, 10 (21%) of whom had simultaneous ligation of a clinically palpable varicocele. Specific attention was focused on the development of postoperative testicular atrophy and hydrocele and the analysis of postoperative semen parameters. RESULTS: No patient developed postoperative testicular atrophy or hydrocele. No statistically significant difference existed in postoperative seminal parameters between those patients who had vasal reconstruction alone and those who had a combined procedure. CONCLUSIONS: In the hands of an experienced microsurgeon, simultaneous vasal reconstruction and varicocele ligation is a management strategy that has an excellent safety profile. This approach is not recommended for the occasional microsurgeon.

Presence of mature sperm in testicular parenchyma of men with nonobstructive azoospermia: prevalence and predictive factors.

OBJECTIVES: Hitherto, patients with testicular dysfunction and azoospermia had to resort to adoption, donor sperm insemination, or child-free living. The realization that a proportion of such men harbor spermatozoa in their testicular parenchyma, combined with the ability of intracytoplasmic sperm injection (ICSI) to effect pregnancy with single sperm, has prompted male infertility clinicians to explore testicular sperm extraction (TESE) in this patient population. We sought to investigate the likelihood of finding spermatozoa during TESE from men presenting with nonobstructive azoospermia and to define if any factors existed that were predictive of eventual sperm presence or absence. METHODS: Thirty patients with nonobstructive azoospermia underwent TESE and simultaneous formal testis biopsy, cytologic analysis, and wet preparation analysis. Tissue obtained from TESE was analyzed according to a rigorous protocol, followed by exhaustive searching by trained embryologists. RESULTS: Twenty-one patients (70%) had spermatozoa found on testicular tissue analysis. Neither patient age nor follicle-stimulating hormone (FSH) level was predictive of the ability to find sperm. With regard to histologic pattern, 50% of men with Sertoli cell-only, 75% of patients with maturation arrest, and 100% of patients with spermatids seen on histologic analysis had sperm retrieved from their testicular tissue during TESE. Absence of sperm on cytologic smear and wet preparation analysis failed to predict the presence of sperm on formal testicular tissue analysis in 40% of patients. CONCLUSIONS: Men with nonobstructive azoospermia may have mature spermatozoa present within their testicular parenchyma. Relying on these data, patients should not be excluded from TESE based on serum FSH level, age, prior histopathologic pattern, or cytology/wet preparation results. These figures will allow clinicians to counsel patients with nonobstructive azoospermia informatively regarding TESE and their chances of having testicular sperm retrieved.

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Expanding the paradigm for plaque development in Peyronie's disease.

Despite centuries of recognition, Peyronie's disease remains somewhat of an enigma. Conventional wisdom suggests that trauma to the erect or semierect penis is the inciting event that sets off a cascade of events at the cellular level that results in localized fibrosis of the tunica albuginea. However, many questions remain unanswered at this juncture among the most important of which are why do so few men manifest this condition? Why is there such an ethnic predilection? What are the cofactors that along with penile trauma lead to plaque development. Historically, cytokine overexpression, autoimmune and genetic factors have been cited as contributors. This treatise endeavors to conduct an evidence-based assessment of the literature as it pertains to the pathophysiology of Peyronie's disease. Furthermore, an effort is made to evaluate contemporary literature pertaining to novel concepts in Peyronie's disease pathogenesis including NOS alterations, free radical generation, microarray analysis, pathogen involvement and animal model development. In conclusion, it is likely that in the near future we will see dramatic developments in our understanding of this condition.

Comparison of in-patient and out-patient penile prosthesis surgery.

Between December 1996 and December 1998, 79 inflatable penile implant insertions have been performed at our institution by a single surgeon. The objective of this analysis was to compare our in-patient and out-patient experience with penile prosthesis insertion with respect to ease of performance and complication profiles. Data was collected in a prospective manner for both groups (in-patient, n = 33 and out-patient, n = 46). The two groups were compared with respect to intra-operative blood loss, operative time, time lost from work, narcotic use and complication rates. Both groups of patients experienced similar operative blood loss, essentially identical operative times, time lost from work and narcotic use. Most importantly, overall complication rates were 6% for the in-patient group and 4% for the out-patient group. Inflatable penile implant surgery is feasible in an ambulatory surgical setting. There is no difference in complication rates, loss of time from work, or intra-operative and post-operative course. Furthermore, there is a significant saving at our institution by performing the procedure in an out-patient fashion. In-patient prosthetic surgery is reserved for secondary procedures following a prior implant infection or primary implants in men with significant co-morbidities that require in-patient postoperative monitoring.

Development of a mathematical model for the prediction of the area of venous leak.

Erectile dysfunction (ED) is an increasingly prevalent medical problem, affecting up to 50% of men aged between 40 and 70-y-old. Many cases are vasculogenic and some of these stem from the inability of the penis to store blood during erection due to leak into the venous system, termed corporo-venocclusive dysfunction (CVOD). The area of leakage during erection could be the most direct measure of erectile function but has not been investigated before. We have developed a simple mathematical model to determine the area of leak during erection and have tested it on data from both normal men (n=3) and men with venogenic impotence (n=16) undergoing dynamic infusion cavernosometry (DIC). The area of leak in the impotent group is significantly greater than in normal men at intracorporal pressures above 30 mmHg and reaches a plateau between 60 and 90 mmHg. Based on this study, we suggest that it may be necessary only to perform DIC at intracorporal pressures between 60 and 90 mmHg.

The hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy.

OBJECTIVE: Despite the advent of the nerve-sparing radical retropubic prostatectomy (NSRRP) a significant number of men still suffer from post radical prostatectomy impotence. The purpose of this study was to investigate the pathogenesis of erectile dysfunction following NSRRP and to define the previously reported vascular mechanism. Furthermore, it was our goal to clarify the respective contributions of arterial and venous components. PATIENTS AND METHODS: Sixteen potent males with localized prostate carcinoma underwent dynamic infusion cavernosometry preoperatively to assess arterial and venous hemodynamics. Ten of these men were impotent following the operation and had repeat cavernosometric evaluation six months postoperatively. RESULTS: On cavernosometry all 10 patients had arterial insufficiency on at least one side, six patients had bilateral changes. The mean reduction in CAOP was 50% (range 30-70%). Four patients met criteria for the diagnosis of corporovenocclusive dysfunction on cavernosometry. CONCLUSIONS: These data strongly support a vascular mechanism in the genesis of post-NSRRP impotence. This mechanism is predominantly arterial in nature, but some men have a mixed pattern with both arterial and venous components. The postoperative arterial insufficiency may be the result of intraoperative injury to the accessory pudendal artery. The exact means by which CVOD develops in this situation remains unclear at this time.

Congruence between veno-occlusive parameters during dynamic infusion cavernosometry: assessing the need for cavernosography.

While dynamic infusion cavernosometry (DIC) is being performed with increasing rarity, some centers continue to use this investigation modality. Cavernosography may be utilized to identify the location of patent venous channels in men with venous leak. In an era when venous ligation surgery is being performed with less frequency, the role of cavernosography has been questioned. This study was conducted to define the congruence between the three parameters (flow-to-maintain (FTM), pressure decay (PD) and cavernosography) used in the diagnosis of venous leak during DIC. Established values for the three parameters were utilized and the diagnosis of venous leak was based upon the FTM measurement. All studies were performed using a vasoactive agent-redosing schedule. Cavernosography was conducted using a nonionic contrast agent at an intracorporal pressure of 90 mmHg. In patients with an elevated FTM value, 24% had a normal PD recorded, all of whom had FTM values <10 ml/min. The Pearson correlation coefficient for the relationship between FTM and PD was 0.58 (P=0.025). In all, 36 patients (54%) had an abnormal cavernosogram (CG). All patients who had positive findings on CG had elevated FTM values. On the other hand, 46% of patients with abnormal FTM values had a normal CG. This analysis indicates that almost one-half of men with venous leak diagnosed at the time of DIC based on FTM measurement will fail to have any veins visualized on cavernosography. These data further undermine the value of cavernosography, particularly in men with low-grade venous leak.

Perturbation of cell cycle regulators in Peyronie's disease.

Peyronie's disease is a fibromatosis of the tunica albuginea, characterized by development of a plaque consisting primarily of collagen. It has been suggested that trauma to the erect penis is the inciting event. More recent research has focused on the cellular events leading to the dysregulated wound healing and plaque formation. Previous work has shown chromosomal aneusomies and this combined with an increased S-phase in plaque derived cell cultures suggests a perturbation in the cell cycle in this condition. The p53 protein has been shown to be an important cell cycle regulator and pro-apoptotic factor. Aberrant p53 function leading to cell immortalization and proliferation has been implicated in several human malignancies. We hypothesized that abnormal p53 function may explain the high proliferative ability of fibroblasts derived from Peyronie's plaques. This study was undertaken to study the presence and function of p53 and its downstream elements (p21, mdm-2) in Peyronie's disease cell cultures. Plaque-derived fibroblasts have been established in culture and characterized. These cells and control neonatal foreskin fibroblasts were subjected to 5 Gy of gamma radiation to induce DNA damage. After fixation, antibodies to p53 and its transcriptional elements were used to stain irradiated and non-irradiated cells and levels of p53, p21 and mdm-2 were quantified using combined immunofluorescence and flow cytometry. Non-irradiated plaque fibroblasts demonstrated the presence of p53, p21 and mdm-2 at baseline. In control foreskin fibroblasts no p53 or mdm-2 were detectable at baseline. In irradiated foreskin-derived cells significant changes in all elements were demonstrated indicating a fully functional p53 pathway and cell cycle checkpoint system in these cells. In contrast, plaque-derived cells showed no such alterations in levels of cell cycle regulators following irradiation. This is highly suggestive of an aberration of the p53 pathway in plaque-derived fibroblasts. Peyronie's plaque-derived fibroblasts demonstrated stabilization and defunctionalization of p53 protein combined with appropriate responses of its transcriptional elements. These findings may explain the high cell proliferation rates in these cells and suggests a role for perturbation of the p53 pathway in the pathogenesis of Peyronie's disease.

Peyronie's disease cell culture models: phenotypic, genotypic and functional analyses.

Peyronie's disease is a fibromatosis of the tunica albuginea. While trauma is believed to be the inciting event, the exact pathophysiology of this condition is unknown. In vitro analysis of cell biology can shed light on the pathogenesis of medical conditions and has been used for many decades as a research tool. We have established a cell culture model, which we have used to study the pathobiology of cells derived from Peyronie's disease plaque tissue. In 10 separate cell cultures derived from different individuals, these cells have demonstrated consistent phenotypic, genotypic and functional alterations. In neither of the control cell cultures, neonatal foreskin fibroblasts and normal tunica-derived fibroblasts have any of the above aberrations been demonstrated. The cells studied have been shown to be fibroblasts in nature with a sub-population of myofibroblasts present in culture. The Peyronie's disease plaque tissue-derived fibroblasts have demonstrated (i) consistent morphologic transformation (ii) increased S-phase on flow cytometry (iii) decreased dependence on culture medium (iv) cytogenic instability (v) excess production of fibrogenic cytokines and (vi) stabilization and dysfunctionalization of p53. Further refinement of this model and future analyses may permit an increased understanding of the pathogenesis of this condition and allow the development of therapeutic strategies.

Inhibition of Peyronie's plaque fibroblast proliferation by biologic agents.

Peyronie's disease is a fibromatosis of the tunica albuginea which affects up to 2% of men. Plaque development is believed to result, at least in part, from fibroblast proliferation and excess collagen deposition. Numerous oral and intralesional therapies have been used, including verapamil, colchicine and steroids. The purpose of this study was to investigate the in vitro effects of prostaglandin-E1 (PGE1), verapamil and colchicine on the proliferation rates of fibroblasts derived from Peyronie's disease tissue. Using tissue culture, multiple cell lines comprising fibroblasts from Peyronie's plaque, normal tunica and foreskin were established. Cells of low passage were removed from the parent culture and incubated with varying concentrations of PGE1 (0.1-10 mg/ml), verapamil (10-1000 mg/ml), and colchine (2.5 mg/ml). Proliferation was assessed at 48, 72 and 96 hours using the Vybrant MTT cell proliferation and then compared to control cells. Six plaque lines and 5 normal tunical cell lines were established. These cell lines exhibited excellent linear growth in culture media alone. Co-culture wih PGE1 resulted in no significant inhibition at 0.1 and 1 mg/ml, but a mean inhibition of 60.6+/-11.5% at a concenrtation of 10 mg/ml was noted. Similar inhibition was noted with verapamil at 100 and 1000 mg/ml with a mean inhibition of 65.2+/-10.6%. Colchicine resulted in a mean inhibition of 28% at a concentration of 2.5 mg/ml. Maximum inhibition occurred at 96 hours in all cases. There was no statisitically significant difference in proliferation rates between plaque and normal tunical cell lines. We have developed an in vitro model to assess the effects of biologically active agents on the growth of fibroblasts derived from Peyronie's disease tissue. Our data suggests that PGE1, verapamil, and colchicine inhibit in vitro proliferation of fibroblasts at specific concentrations. Refinement and application of this knowledge may allow the development of useful pharmacologic strategies for men with PD.

Chromosomal instability is demonstrated by fibroblasts derived from the tunica of men with Peyronie's disease.

Peyronie's disease is a fibrotic disorder, a condition characterized by cellular proliferation and excess extracellular matrix production. Previous work in related conditions has demonstrated chromosomal instability. This investigation was undertaken to analyze fibroblasts derived from Peyronie's disease tunical tissue for abnormalities of chromosome number and progression of cytogenetic aberrations during cell culture. Tunical tissue was excised from men with Peyronie's disease from both plaque and nonplaque tissue and cells were explanted in culture. Control cells were derived from both neonatal foreskins and normal tunica from men with congenital penile curvature. Fluorescent in situ hybridization was used to probe for chromosomes 7, 8, 17, 18, X and Y. Control cells demonstrated normal copy number for all chromosomes analyzed. In contrast, Peyronie's disease plaque-derived fibroblasts demonstrated frequent aneusomies in chromosomes 7, 8, 17, 18 and X and recurrent deletions of chromosome Y. Peyronie's disease nonplaque tunica-derived fibroblasts demonstrated infrequent chromosomal changes early in culture; however, with repeated passaging the majority of cell cultures demonstrated aneusomies in at least one chromosome. These data indicate that Peyronie's disease plaque-derived fibroblasts have consistent aneusomies even at early passage and that nonplaque tunica-derived cells from men with Peyronie's disease also demonstrate chromosomal instability. This suggests that the tunica albuginea of men with Peyronie's disease may be predisposed to undergoing unregulated fibrosis. These findings confirm the transformed nature of the Peyronie's disease tunical fibroblasts studied in this analysis. While the etiology of these findings is not clear, it is likely that these pathobiological characteristics contribute to the pathophysiology of this disease process.

Peyronie's disease fibroblasts demonstrate tumorigenicity in the severe combined immunodeficient (SCID) mouse model.

Peyronie's disease is a localized connective tissue disorder, caused by trauma to the erect penis, which results in cellular proliferation and excess extracellular matrix production within the tunica albuginea of the penis. We have previously demonstrated that cells derived from Peyronie's disease plaque tissue demonstrate increased cell growth, increased S-phase on flow cytometry, stabilization and inactivation of p53, and consistent morphologic transformation, all suggesting that these cells are biologically transformed. Severe combined immunodeficient (SCID) mice have been used extensively to study the pathobiology of malignant and benign tissue and cells. This study was undertaken to determine if Peyronie's derived fibroblasts had the potential to demonstrate tumorigenicity in the SCID mouse model, thus confirming their biologically transformed nature. Cultured fibroblasts were derived from three sources, namely, plaque tissue excised from men with Peyronie's disease, tunical tissue excised from young men with congenital penile curvature and neonatal foreskins. BALB/C SCID mice were divided into three groups and each group was inoculated with cultured fibroblasts from each of the three different sources. All animals were evaluated regularly and maintained in isolation for a period of 3 months following inoculation. All SCID mice inoculated with cells derived from Peyronie's disease plaque tissue (n=10) developed subcutaneous nodules at a mean time period of 2.5+/-0.5 months following injection. The mean maximum dimension and weight of the nodules at the time of killing the animal was 1.1+/-0.2 cms and 0.6+/-0.2 g, respectively. Histologically, the nodules were composed of large pleomorphic epithelioid cells with a high mitotic activity, which were negative for cytokeratin but positive for vimentin. None of the SCID mice inoculated with cells cultured from either normal tunica (n=5) or foreskin (n=5) developed subcutaneous nodules. In conclusion, the tumorigenic nature of Peyronie's disease plaque-derived fibroblasts sheds further light on the pathobiologic characteristics of these cells. Specifically, these data confirm that cells cultured from Peyronie's disease plaque are biologically transformed. Future refinement and study of this animal model may permit a more complete understanding of the pathophysiology of Peyronie's disease and fibromatoses in general. Furthermore, such an animal model may, in the future, allow a more ready evaluation of the therapeutic interventions for Peyronie's disease.

Should all infertile males undergo urologic evaluation before assisted reproductive technologies? Two cases of testicular cancer presenting with infertility.

OBJECTIVE: To report two cases of testicular cancer in patients presenting with infertility. DESIGN: Case reports. SETTING: University-affiliated urology practice. PATIENT(S): Two men presenting with infertility. INTERVENTION(S): Complete history and physical, hormonal assays, semen analysis, scrotal ultrasound, radical orchiectomy. MAIN OUTCOME MEASURE(S): Testicular pathology specimens. RESULT(S): Testicular cancer was diagnosed in two men sent to a urology clinic for infertility treatment. CONCLUSION(S): A thorough evaluation should be completed in all males in couples presenting with infertility.

Drugs for the treatment of impotence.

Penile erection is a complex neurovascular event that represents a balance between corporal smooth muscle relaxation and contraction. This balance is determined by the interaction between proerectile and antierectile neurotransmitters. It is believed that nitric oxide is the primary erectogenic neurotransmitter and that noradrenaline (norepinephrine) is the primary erectolytic neurotransmitter. There are a number of pharmacological approaches to the management of erectile dysfunction and manipulation of the neurotransmitter systems. These involve direct delivery of drugs into the erectile chambers (intracavernosal injection therapy), administration of medications into the urethra (transurethral delivery), application of medications to the skin (transdermal delivery) and it is hoped that oral agents will be available in the very near future. This article reviews the world literature on the medications that have been investigated to date and their delivery routes.

Priapism: etiology and management.

Priapism is a urologic emergency. All patients should receive prompt urologic consultation. Management is based on prompt recognition, differentiation between low- and high-flow priapism, reversal of any potential precipitating factors, and the use of corporal aspiration/irrigation combined with intracavernosal alpha-agonist injection therapy. It cannot be over-emphasized that severely prolonged erections are associated with the development of irreversible problems with erectile function and, therefore, immediate and aggressive management is mandatory.

Emergency management of blunt testicular trauma.

OBJECTIVE: Severe blunt testicular trauma is an infrequently reported consequence of injury, yet it is associated with significant sequelae. This case series evaluates the characteristics of patients with severe blunt testicular trauma, assesses the role of ultrasonography in their management, and offers an evaluation algorithm for use by both emergency and urology personnel. METHODS: A retrospective review was conducted of ten patients who had severe blunt testicular injuries referred for urologic evaluation over a seven-year period at a level 1 trauma center. Attention was focused on ultrasonographic results, operative findings, and testicular salvage rates. RESULTS: With the exception of two motorcycle crash victims, patients presented in a delayed fashion (mean 3.5 days; range 1-5 days). Most (6/10) patients had true testicular rupture, all were explored urgently, and there was a 100% testicular salvage rate. Of the eight patients who had preoperative ultrasonographic examination, two were reported to show testicular rupture, but on exploration only one in fact had a tunica albuginea tear. Six patients had ultrasonographic examinations that revealed nonspecific abnormalities but failed to show testicular rupture; three had testicular rupture. CONCLUSIONS: Ultrasonography cannot be relied on to accurately diagnose rupture of the testis in high-risk patients. However, testicular rupture is universally associated with an abnormal ultrasonography scan, albeit commonly yielding nonspecific findings. A high level of suspicion is mandatory with high-energy transfer mechanisms. Since a significant delay in presentation is not unusual, early exploration is warranted in the setting of high risk and provides an excellent chance of testicular salvage. Injuries associated with normal testicular ultrasonography may be managed conservatively.