Inflammatory Expression Profiles in Bladder Exstrophy Smooth Muscle: Normalization Over Time.

OBJECTIVE: To test the hypothesis that phenotypes in bladder exstrophy result from alterations in detrusor smooth muscle cell (SMC) gene expression. METHODS: We generated primary human bladder smooth muscle cell lines from patients with classic bladder exstrophy (CBE) undergoing newborn closure (n = 6), delayed primary closure (n = 5), augmentation cystoplasty (n = 6), and non-CBE controls (n = 3). Gene expression profiles were then created using RNA sequencing and characterized using gene set enrichment analysis (GSEA). RESULTS: We identified 308 differentially expressed genes in bladder exstrophy SMC when compared to controls, including 223 upregulated and 85 downregulated genes. Bladder exstrophy muscle cell lines from newborn closure and primary delayed closures shared expression changes in 159 genes. GSEA analysis revealed increased expression in the inflammatory response and alteration of genes for genitourinary development in newborn and delayed closure SMC. However, these changes were absent in SMC from older exstrophy patients after closure. CONCLUSION: Bladder exstrophy SMC demonstrate gene expression changes in the inflammatory response and genitourinary development. However, gene expression profiles normalized in exstrophy SMC from older patients after closure, suggesting a normalization of exstrophy SMC over time. Our in vitro findings regarding the normalization of exstrophy SMC gene expression following bladder closure suggest that the development of poor detrusor compliance in bladder exstrophy has a complex multifactorial etiology. Taken together, our findings suggest that alterations in SMC gene expression may explain abnormalities in the exstrophy bladder seen prior to and immediately after closure and suggest that surgical closure may allow exstrophy SMC to normalize over time.

Diagnosis of hemophilia in newborn circumcision: A case presentation.

Circumcision is often the earliest surgery performed in a young male's life. Though complications in this procedure are rare, prolong postoperative bleeding may be the first sign of undiagnosed hemophilia. Hemophilia is a rare X-linked bleeding disorder and if not treated prophylactically or promptly during surgical intervention can be fatal. In this case presentation we describe the diagnosis of hemophilia in a child presenting with postoperative bleeding from circumcision. We review the literature regarding the history of this disease with early surgery and highlight the current treatments.

Novel Anatomical Observations of the Prostate, Prostatic Vasculature and Penile Vasculature in Classic Bladder Exstrophy Using Magnetic Resonance Imaging.

PURPOSE: We used magnetic resonance imaging to define the innate pelvic neurovascular course and prostatic anatomy in infants with classic bladder exstrophy before the pelvis was altered by surgery. MATERIALS AND METHODS: Pelvic magnetic resonance imaging was performed in male infants with classic bladder exstrophy and compared to a group of age matched controls. Data collected included prostatic dimensions as well as course of the prostatic artery, periprostatic vessels and pudendal neurovasculature. RESULTS: The prostate was larger in the transverse (p <0.001) and anteroposterior (p <0.001) dimensions in patients with classic bladder exstrophy compared to those with normal prostates but was smaller in the craniocaudal dimension (p <0.001). This finding resulted in a larger calculated prostate volume in patients with classic bladder exstrophy compared to controls (p = 0.015). The pelvic vasculature and prostatic artery followed a similar course in patients with classic bladder exstrophy and controls. Relative to each other, the lateral to medial course of the prostatic arteries in males with classic bladder exstrophy was less pronounced than in normal males. A similar externally rotated pattern was seen when both sides of the pudendal vasculature were compared in males with classic bladder exstrophy. CONCLUSIONS: The prostate in infants with classic bladder exstrophy has a consistent configuration and dimensions that differ from those in normal infants. When both sides are compared, the periprostatic vasculature and penile sensory neurovascular bundles are externally rotated in infants with classic bladder exstrophy. However, these components course along the same landmarks as in normal patients.

Novel Observations of Female Genital Anatomy in Classic Bladder Exstrophy Using 3-Dimensional Magnetic Resonance Imaging Reconstruction.

PURPOSE: Understanding the distinct female anatomy in classic bladder exstrophy is crucial for optimal reconstructive and functional outcomes. We present novel quantitative anatomical data in females with classic bladder exstrophy before primary closure. MATERIALS AND METHODS: 3-Dimensional reconstruction was performed in patients undergoing pelvic magnetic resonance imaging, and pelvic anatomy was characterized, including measurements of the vagina, cervix and erectile bodies. RESULTS: We examined magnetic resonance imaging of 5 females (mean age 5.5 months) with classic bladder exstrophy and 4 age matched controls (mean age 5.8 months). Mean distance between the anal verge and vaginal introitus was greater in patients with classic bladder exstrophy (2.43 cm) than in controls (1.62 cm). Mean total vaginal length in patients with classic bladder exstrophy was half that of controls (1.64 cm vs 3.39 cm). All 4 controls had posterior facing cervical ora, while 4 of 5 females with exstrophy had anterior facing cervical ora located in the anterior vaginal wall. Lateral deviation of the cervical ora was also seen in all 5 patients with classic bladder exstrophy but in only 1 control. Clitoral body length was comparable in both groups (26.2 mm and 28.0 mm). However, the anterior cavernosa-to-posterior (pelvic rami associated) cavernosa ratio was much greater in patients with classic bladder exstrophy (6.4) compared to controls (2.5). CONCLUSIONS: This study uncovers the uniquely novel finding that contrary to their male counterparts, females with classic bladder exstrophy have the majority of the clitoral body anterior to the pelvic attachment. This discovery has surgical and embryological implications.

Cytotoxic Necrotizing Factor-1 (CNF1) does not promote E. coli infection in a murine model of ascending pyelonephritis.

BACKGROUND: Urinary tract infections (UTI) are among the most common and costly infections in both hospitalized and ambulatory patients. Uropathogenic E. coli (UPEC) represent the majority of UTI isolates and are a diverse group of bacteria that utilize a variety of virulence factors to establish infection of the genitourinary tract. The virulence factor cytotoxic necrotizing factor-1 (CNF1) is frequently expressed in clinical UPEC isolates. To date, there have been conflicting reports on the role of CNF1 in the pathogenesis of E. coli urinary tract infections. RESULTS: We examined the importance of CNF1 in a murine ascending kidney infection/ pyelonephritis model by performing comparative studies between a clinical UPEC isolate strain and a CNF1-deletion mutant. We found no alterations in bacterial burden with the loss of CNF1, whereas loss of the virulence factor fimH decreased bacterial burdens. In addition, we found no evidence that CNF1 contributed to the recruitment of inflammatory infiltrates in the kidney or bladder in vivo. CONCLUSIONS: While further examination of CNF-1 may reveal a role in UTI pathogenesis, our data casts doubt on the role of CNF-1 in the pathogenesis of UPEC UTI. As with other infections, different models and approaches are needed to elucidate the contribution of CNF1 to E. coli UTI.

Repair of Vesicocutaneous and Urethrocutaneous Fistulae with Rectus Muscle Flap in a Bladder Exstrophy Patient.

Urinary continence can be achieved in up to 90% of patients with bladder exstrophy. However, select patients remain incontinent despite modern reconstruction. Repeat operations for continence combined with the congenital pelvic abnormalities of exstrophy put patients at risk for urinary fistula formation. We report the use of a rectus muscle flap in the repair of two concomitant vesicocutaneous and urethrocutaneous fistulae in a patient with classic bladder exstrophy.

Upper Pole Heminephrectomy Versus Lower Pole Ureteroureterostomy for Ectopic Upper Pole Ureters.

PURPOSE OF REVIEW: Ureteral duplication and ectopic upper pole ureters are commonly associated with renal pathology, including vesicoureteral reflux, obstruction, infection, and renal function loss. There remains no consensus on the most appropriate management of these complex patients. In this review, we sought to compare existing data on upper pole heminephrectomy with ipsilateral ureteroureterostomy. RECENT FINDINGS: Application of magnetic resonance imaging and minimally invasive techniques have led to changes in the diagnosis and treatment of ectopic upper pole ureters. Recent studies have highlighted the safety of laparoscopic and robot-assisted upper pole heminephrectomy and ureteroureterostomy. Minimally invasive approaches to ectopic upper pole ureters appear safe and effective, with complication rates remaining low. Minimally invasive upper pole heminephrectomy carries a higher risk of lower pole function loss. Both upper pole heminephrectomy and ureteroureterostomy carry a small risk of additional surgery on the bladder and remnant ureter.

Cost and radiation exposure in the workup of febrile pediatric urinary tract infections.

BACKGROUND: Technetium-99m dimercaptosuccinic acid (DMSA) scans are often used in the evaluation of pediatric patients with febrile urinary tract infections (UTIs). Given the prevalence of febrile UTIs, we sought to quantify the cost, radiation exposure, and clinical utility of DMSA scans when compared with dedicated pediatric renal ultrasounds (RUSs). MATERIALS AND METHODS: An institutional review board approved retrospective study of children under the age of 18 years evaluated at our institution for febrile UTIs between the years 2004-2013 was conducted. The patients had to meet all of the following inclusion criteria: a diagnosis of vesicoureteral reflux, a fever >38°C, a positive urine culture, and evaluation with a DMSA scan and RUS. A chart review was used to construct a cost analysis of technical and professional fees, radiographic results, and radiation dose equivalents. RESULTS: Overall, 104 children met the inclusion criteria. A total of 122 RUS and 135 DMSA scans were performed. The technical costs of a DMSA scan incurred a 35% cost premium as compared to an RUS. The average effective radiation dose of a single DMSA scan was 2.84 mSv. New radiographic findings were only identified on 7% of those patients who underwent greater than 1 DMSA scan. CONCLUSIONS: The utility of the unique information acquired from a DMSA scan as compared to a RUS in the evaluation of febrile UTI must be evaluated on an individual case-by-case basis given the increased direct costs and radiation exposure to the patient.

Use of muscle pedicle flaps for failed bladder neck closure in the exstrophy spectrum.

PURPOSE: The authors have reviewed the use of muscle pedicle flaps for the treatment of failed bladder neck closure in exstrophy spectrum patients. METHODS: A retrospective review of all exstrophy spectrum patients who underwent continence procedures with the use of muscle pedicle flaps at our institution during the last 15 years was performed. Patient characteristics, surgical history, and outcomes, including complications, continence, morbidity, and infection, were assessed. The authors utilized muscle pedicle flaps in eight exstrophy patients, including four patients with classic bladder exstrophy and four patients with cloacal exstrophy. Seven of eight patients had failed at least one prior bladder neck closure, and they had undergone a median of three prior urologic procedures. To achieve continence, five rectus muscle flaps and three gracilis muscle flaps were utilized in combination with bladder neck closure. RESULTS: There were no major intraoperative or postoperative complications. All patients were initially continent, and after a median follow-up of 18.7 months seven of eight patients were continent. One patient required continent urinary stoma revision and one patient developed perineal incontinence after perineal trauma. No patients required revision of, or additional, continence procedures at the bladder neck. DISCUSSION: The use of pedicle muscle flaps appears to be a safe and feasible option for exstrophy spectrum patients with failed bladder neck closure. Although achieving continence can be difficult in this population, use of muscle flaps and bladder neck closure is a viable and effective option in this challenging subset of patients.

Duplicated Renal Collecting System With Ectopic Ureter in Female Bladder Exstrophy: A Case Report.

Bladder exstrophy is a rare major birth defect which requires specialized surgical care. Associated genitourinary tract anomalies are extremely rare in this population, yet significantly impact surgical planning and outcomes. In this case, a full-term newborn girl with a prenatal diagnosis of classic bladder exstrophy was found to have a complete duplicated left collecting system with an ectopic ureter inserted to urethral plate. The patient underwent modern staged repair of exstrophy with bilateral anterior innominate osteotomies and concomitant ureteral reimplantation-the first reported case of ureteral reimplantation at the time of initial closure in a newborn.

Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk.

Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.