Carlos R. Estrada

MECHANICAL RELIABILITY AND SAFETY OF, AND PATIENT SATISFACTION WITH THE AMBICOR INFLATABLE PENILE PROSTHESIS: RESULTS OF A 2 CENTER STUDY

PURPOSE We reviewed the experience with the 2-piece Ambicor penile prosthesis (American Medical Systems, Minnetonka, Minnesota) at 2 medical centers to investigate its mechanical reliability and complication rates as well as patient and partner satisfaction with the device. MATERIALS AND METHODS From 1995 through 1999, 131 men underwent implantation of an Ambicor penile prosthesis at 2 medical centers. We performed a 3-part study consisting of a retrospective clinical record review, mailed patient and partner questionnaire, and mailed modified patient and partner Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire. Mean followup was 43.4 months (range 12 to 73). RESULTS All 131 men had a history consistent with an organic etiology of erectile dysfunction, including vascular disease in 62%, radical retropubic prostatectomy in 17%, Peyronies disease in 15%, neophallus construction in 4% and radical pelvic surgery in 2%. Mean patient age was 56.8 years (range 22 to 76) at implantation. Overall there were complications in 10 cases (7.6%), including infection, hematoma and mechanical failure in 6 (4.6%), 1 (0.7%) and 3 (2.3%), respectively. A total of 112 men (85%) and 91 partners completed the questionnaire. All patient respondents still had an Ambicor prosthesis implanted and 96.4% had erection suitable for coitus. Overall patient and partner satisfaction was 96.4% and 91.2%, respectively. Of the respondents 92.9% of patients and 90.1% of partners would recommend the device to others. Of the 85 men (65%) and 46 partners who completed the modified Erectile Dysfunction Inventory of Treatment Satisfaction survey 90.6% and 82.6%, respectively, were satisfied or very satisfied overall with the penile prosthesis. CONCLUSIONS The Ambicor penile prosthesis is associated with a low complication rate and reliable mechanical function. High satisfaction was reported by patients and partners.

Nomograms for Predicting Annual Resolution Rate of Primary Vesicoureteral Reflux: Results From 2,462 Children

PURPOSE We determined the resolution rate of vesicoureteral reflux and the factors that influence it to formulate nomograms to predict the probability of annual resolution for individual cases of reflux. MATERIALS AND METHODS We studied 2,462 children with primary vesicoureteral reflux diagnosed between 1998 and 2006. Cox proportional hazards regression was used to model time to resolution as a function of statistically significant demographic and clinical variables. The resulting model was used to construct nomograms predicting the annual cumulative probability of reflux resolution. RESULTS Multivariate analysis showed that all cases of unilateral reflux resolved earlier than female bilateral reflux (HR 1.42, p <0.001). Additionally age less than 1 year at presentation (HR 1.31, p <0.001), lower reflux grade (2.96, p <0.001 for grade I; 2.28, p <0.001 for grade II; 1.63, p <0.001 for grade III), reflux diagnosed on postnatal evaluation for prenatal hydronephrosis or sibling screening (1.24, p = 0.002) and single ureter (1.55, p <0.001) were associated with significantly earlier resolution of reflux. Specific predicted cumulative probabilities of reflux resolution at annual intervals from diagnosis (1 to 5 years) were calculated for every possible combination of the significant variables. CONCLUSIONS Our analyses demonstrate that resolution of vesicoureteral reflux is dependent on age at presentation, gender, grade, laterality, mode of clinical presentation and ureteral anatomy. We constructed nomogram tables containing estimates of annual reflux resolution rate as a function of these variables. This information is valuable for clinical counseling and management decisions.

Ultrasound Versus Computerized Tomography for Evaluating Urolithiasis

PURPOSE We prospectively evaluated the precision of ultrasound and computerized tomography to diagnose urinary stones in children and determined whether these differences in radiological findings have any impact on clinical management. MATERIALS AND METHODS A total of 50 consecutive patients with suspected urolithiasis underwent computerized tomography and ultrasound. Two radiologists reviewed each study independently in blinded fashion. When a difference in findings was detected, 8 pediatric urologists reviewed the case. Clinical management was based on the results of each radiological test independently. Statistical analysis was performed using Fishers exact test. RESULTS Compared to computerized tomography ultrasound had 76% sensitivity and 100% specificity. In 8 patients stone(s) seen on computerized tomography was not seen on ultrasound. The average size of missed stones was 2.3 mm. In 7 patients computerized tomography showed stones bilaterally but stone was seen on only 1 side on ultrasound. When evaluating the clinical impact, the ultrasound/computerized tomography discrepancy did not result in any significant change in clinical management except in 4 cases. In these cases ultrasound findings suggested that additional imaging was required and, thus, stone(s) in the distal ureter would have been identified on subsequent imaging. CONCLUSIONS Although computerized tomography is more sensitive for detecting urolithiasis than ultrasound, the difference in usefulness between the 2 radiological tests may not be clinically significant. Given concerns for the potentially harmful cumulative long-term effect of radiation, ultrasound should be considered the first imaging test in children with suspected urolithiasis.

Vesicoureteral reflux and urinary tract infection in children with a history of prenatal hydronephrosis - should voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis?

PURPOSE The clinical relevance of prenatal hydronephrosis is not well-defined. We determined the risk of febrile urinary tract infection in the absence of screening for vesicoureteral reflux, and whether postnatal voiding cystourethrography should be performed in patients with a history of prenatal hydronephrosis and postnatally persistent Society for Fetal Urology grade II hydronephrosis. MATERIALS AND METHODS From a longitudinal database of patients with prenatal hydronephrosis maintained since 1998 we identified those with postnatally persistent grade II hydronephrosis. This cohort was divided into patients who were and were not screened with an initial voiding cystourethrogram. The rates of vesicoureteral reflux and development of febrile urinary tract infection were determined. RESULTS Of 2,076 patients with prenatal hydronephrosis 1,514 had grade II hydronephrosis. Of the patients 76% underwent an initial voiding cystourethrogram and vesicoureteral reflux was found in 28%. There was no relation between laterality of hydronephrosis and incidence of vesicoureteral reflux. There was no difference between nonscreened and screened patients with respect to gender and laterality of hydronephrosis. Urinary tract infection developed in 1.3% of the patients who were screened and did not have vesicoureteral reflux and, therefore, were not receiving antibiotics. Of the screened patients with vesicoureteral reflux who were receiving prophylactic antibiotics urinary tract infection developed in 1.6% at a mean age of 9.4 months. In 363 patients who did not undergo an initial voiding cystourethrogram we estimated (based on the screened population) that 101 would have vesicoureteral reflux and 5 would have a urinary tract infection. However, a febrile urinary tract infection developed in 16 patients (4.4% overall, p <0.0001) at a mean age of 9.3 months. Voiding cystourethrogram performed in these 16 patients revealed vesicoureteral reflux in 12. Of all the patients with a urinary tract infection who were ultimately observed to have vesicoureteral reflux (including those initially screened and those discovered to have reflux after a urinary tract infection) the laterality of hydronephrosis, grade of reflux and laterality of reflux were comparable. CONCLUSIONS In patients with a history of prenatal hydronephrosis who are observed to have postnatally persistent grade II hydronephrosis identification of vesicoureteral reflux and use of prophylactic antibiotics significantly reduce the risk of febrile urinary tract infection. Therefore, we recommend that patients with a history of prenatal hydronephrosis and postnatally persistent hydronephrosis be screened with voiding cystourethrography early in life, and be placed on prophylactic antibiotics until the screening results are known.

Prenatal hydronephrosis: early evaluation.

Purpose of review Fetal hydronephrosis is the most common anomaly detected on antenatal ultrasound examination, and its significance and management remain controversial. This review aims to address the early postnatal evaluation of the child with prenatally diagnosed hydronephrosis. Recent findings The risk of significant urological pathology increases with the severity of prenatal hydronephrosis. The most common underlying conditions are ureteropelvic junction obstruction and vesicoureteral reflux. The use of postnatal ultrasonograpy in all patients with a history of any degree of prenatal hydronephrosis is routine, but ascertaining which patients require postnatal evaluation with a voiding cystourethrogram to investigate for vesicoureteral reflux remains controversial. Mild cases are the most controversial as the risk of pathology is lessened, however the risk of vesicoureteral reflux and consequent febrile urinary tract infection may be significant. Early postnatal evaluation of all children with a history of prenatal hydronephrosis with a voiding cystourethrogram may reduce this risk. No prospective randomized clinical trials are available, however, to adequately address the question of which patients require postnatal evaluation. Summary The postnatal management of prenatal hydronephrosis remains controversial. Sufficient data are lacking to inform patient risk stratification. Therefore, early postnatal evaluation of children with a history of any degree of prenatal hydronephrosis with an ultrasound and voiding cystourethrogram is reasonable and may reduce the risk of febrile urinary tract infection.

Bladder Tissue Regeneration Using Acellular Bi-Layer Silk Scaffolds in a Large Animal Model of Augmentation Cystoplasty

Acellular scaffolds derived from Bombyx mori silk fibroin were investigated for their ability to support functional tissue regeneration in a porcine model of augmentation cystoplasty. Two bi-layer matrix configurations were fabricated by solvent-casting/salt leaching either alone (Group 1) or in combination with silk film casting (Group 2) to yield porous foams buttressed by heterogeneous surface pore occlusions or homogenous silk films, respectively. Bladder augmentation was performed with each scaffold group (6 × 6 cm(2)) in juvenile Yorkshire swine for 3 m of implantation. Augmented animals exhibited high rates of survival (Group 1: 5/6, 83%; Group 2: 4/4, 100%) and voluntary voiding over the course of the study period. Urodynamic evaluations demonstrated mean increases in bladder capacity over pre-operative levels (Group 1: 277%; Group 2: 153%) which exceeded nonsurgical control gains (144%) encountered due to animal growth.In addition, animals augmented with both matrix configurations displayed increases in bladder compliance over pre-operative levels(Group 1: 357%; Group 2: 338%) similar to growth-related elevations observed in non-surgical controls (354%) [corrected]. Gross tissue evaluations revealed that both matrix configurations supported extensive de novo tissue formation throughout the entire original implantation site which exhibited ultimate tensile strength similar to nonsurgical counterparts. Histological and immunohistochemical analyses showed that both implant groups promoted comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent cytokeratin, uroplakin, and p63 protein expression in both matrix groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by synaptophysin-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. Ex vivo organ bath studies demonstrated that regenerated tissues supported by both silk matrices displayed contractile responses to carbachol, α,β-methylene-ATP, KCl, and electrical field stimulation similar to controls. Our data detail the ability of acellular silk scaffolds to support regeneration of innervated, vascularized smooth muscle and urothelial tissues within 3 m with structural, mechanical, and functional properties comparable to native tissue in a porcine model of bladder repair.

All-Trans Retinoic Acid Directs Urothelial Specification of Murine Embryonic Stem Cells via GATA4/6 Signaling Mechanisms

The urinary bladder and associated tract are lined by the urothelium, a transitional epithelium that acts as a specialized permeability barrier that protects the underlying tissue from urine via expression of a highly specific group of proteins known as the uroplakins (UP). To date, our understanding of the developmental processes responsible for urothelial differentiation has been hampered due to the lack of suitable models. In this study, we describe a novel in vitro cell culture system for derivation of urothelial cells from murine embryonic stem cells (ESCs) following cultivation on collagen matrices in the presence all trans retinoic acid (RA). Upon stimulation with micromolar concentrations of RA, ESCs significantly downregulated the pluripotency factor OCT-4 but markedly upregulated UP1A, UP1B, UP2, UP3A, and UP3B mRNA levels in comparison to naïve ESCs and spontaneously differentiating controls. Pan-UP protein expression was associated with both p63- and cytokeratin 20-positive cells in discrete aggregating populations of ESCs following 9 and 14 days of RA stimulation. Analysis of endodermal transcription factors such as GATA4 and GATA6 revealed significant upregulation and nuclear enrichment in RA-treated UP2-GFP+ populations. GATA4−/− and GATA6−/− transgenic ESC lines revealed substantial attenuation of RA-mediated UP expression in comparison to wild type controls. In addition, EMSA analysis revealed that RA treatment induced formation of transcriptional complexes containing GATA4/6 on both UP1B and UP2 promoter fragments containing putative GATA factor binding sites. Collectively, these data suggest that RA mediates ESC specification toward a urothelial lineage via GATA4/6–dependent processes.

The Performance of Silk Scaffolds in a Rat Model of Augmentation Cystoplasty

The diverse processing plasticity of silk-based biomaterials offers a versatile platform for understanding the impact of structural and mechanical matrix properties on bladder regenerative processes. Three distinct groups of 3-D matrices were fabricated from aqueous solutions of Bombyx mori silk fibroin either by a gel spinning technique (GS1 and GS2 groups) or a solvent-casting/salt-leaching method in combination with silk film casting (FF group). SEM analyses revealed that GS1 matrices consisted of smooth, compact multi-laminates of parallel-oriented silk fibers while GS2 scaffolds were composed of porous (pore size range, 5-50 μm) lamellar-like sheets buttressed by a dense outer layer. Bi-layer FF scaffolds were comprised of porous foams (pore size, ~400 μm) fused on their external face with a homogenous, nonporous silk film. Silk groups and small intestinal submucosa (SIS) matrices were evaluated in a rat model of augmentation cystoplasty for 10 weeks of implantation and compared to cystotomy controls. Gross tissue evaluations revealed the presence of intra-luminal stones in all experimental groups. The incidence and size of urinary calculi was the highest in animals implanted with gel spun silk matrices and SIS with frequencies ≥57% and stone diameters of 3-4 mm. In contrast, rats augmented with FF scaffolds displayed substantially lower rates (20%) and stone size (2 mm), similar to the levels observed in controls (13%, 2 mm). Histological (hematoxylin and eosin, Massons trichrome) and immunohistochemical (IHC) analyses showed comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites supported by all matrix groups similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent uroplakin and p63 protein expression in all experimental groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by Fox3-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. In comparison to other biomaterial groups, cystometric analyses at 10 weeks post-op revealed that animals implanted with the FF matrix configuration displayed superior urodynamic characteristics including compliance, functional capacity, as well as spontaneous non voiding contractions consistent with control levels. Our data demonstrate that variations in scaffold processing techniques can influence the in vivo functional performance of silk matrices in bladder reconstructive procedures.

Intralesional verapamil for the treatment of Peyronie's disease: a review

Multiple treatment options have been used for Peyronies disease (PD) including intralesional injection of the calcium antagonist verapamil. The use of verapamil is based on its capacity to alter fibroblast function at several levels, including cell proliferation, extracellular matrix protein synthesis and secretion, as well as collagen degradation. Consequently, calcium antagonists may have the capacity to slow, prevent, or even reverse plaque formation and the progression of PD. The multicenter international experience with intralesional verapamil injection suggests that the majority of men with PD that receive treatment demonstrate durable reduction in pain, decrease in curvature, and improved sexual function. We review the scientific rationale, published literature, clinical experience, and technique of intralesional injection of verapamil.

The effect of manipulation of silk scaffold fabrication parameters on matrix performance in a murine model of bladder augmentation.

Autologous gastrointestinal segments are utilized as the primary option for bladder reconstructive procedures despite their inherent morbidity and significant complication rate. Multi-laminate biomaterials derived from Bombyx mori silk fibroin and prepared from a gel spinning process may serve as a superior alternative for bladder tissue engineering due to their robust mechanical properties, biocompatibility, and processing plasticity. In the present study, we sought to determine the impact of variations in winding (axial slew rate: 2 and 40 mm/s) and post-winding (methanol and lyophilization) fabrication parameters on the in vivo performance of gel spun silk scaffolds in a murine model of bladder augmentation. Three silk matrix groups with distinct structural and mechanical properties were investigated following 10 weeks of implantation including our original prototype previously shown to support bladder regeneration, Group 1 (2 mm/s, methanol) as well as Group 2 (40 mm/s, methanol) and Group 3 (40 mm/s, lyophilization) configurations. Non surgical animals were assessed in parallel as controls. Quantification of residual scaffold area demonstrated that while Group 1 and 2 scaffolds were largely intact, processing parameters utilized for Group 3 led to significantly higher degrees of scaffold degradation in comparison to Group 1. Histological (hematoxylin and eosin, massons trichrome) and immunohistochemical (IHC) analyses showed comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within the original defect site throughout all matrix groups similar to controls. Parallel evaluations demonstrated transitional urothelial formation with prominent uroplakin and p63 protein expression supported by Group 1 and 3 scaffolds, while Group 2 variants supported a thin, immature epithelium composed primarily of uroplakin-negative, p63-positive basal cells. Voided stain on paper analysis revealed similar voiding patterns between all matrix groups; however Group 2 animals displayed substantially lower voided volumes with increased frequency in comparison to controls. In addition, cystometric assessments revealed all matrix groups supported comparable degrees of bladder compliance similar to control levels. The results of this study demonstrate that selective alterations in winding and post-winding fabrication parameters can enhance the degradation rate of gel spun silk scaffolds in vivo while preserving their ability to support bladder tissue regeneration and function.