Search

Objective To review the nature and extent of bladder exstrophy-epispadias related malpractice litigation in the United States.Methods Two legal databases (Nexis Uni, WestLaw) were reviewed for state and federal cases using the terms “bladder exstrophy”, “cloacal exstrophy”, “epispadias”, in combination with “medical malpractice”, or “negligence”, or “medical error”, or “complication”, or “malpractice”, or “tort”. Databases were queried from 1948 to 2022 and reviewed for medical and legal details.Results Our search yielded 16 unique legal cases with 6 fitting established criteria for analysis. Urology and paediatric urologists were named in 50% of cases as were community medical systems. Cause for lawsuit included negligence in surgical performance (50%), primary closure of exstrophy (33%), and post-operative care (50%). Settlement agreement was reached in one case (17%). Outcomes favoured the physician in 60% of trials. Lawsuits alleging negligent surgical performance and/or post-operative care exclusively named urologists with outcomes favouring the surgeon in 66% of cases. The settlement payment (n = 1) was $500,000 and monetary damages (n = 1) equated to $1.3 million.Conclusions Malpractice litigation related to BEEC treatment is rare. Trial outcomes favour the medical provider. Cases that resulted in financial liability successfully alleged avoidable negligence resulting in irreversible physical damage. The authors recommend families with BEEC seek board-certified paediatric urologists experienced in treating this complex and/or Bladder Exstrophy Centers of Excellence. Further, we recommend surgeons treating BEEC properly educate patients and families on the severity of this major birth defect including its lifelong implications and need for surgical revisions.

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Some patients who have seizures that cannot be controlled by medication respond to a ketogenic diet, which is high in fat, low in carbohydrate and protein, and which produces ketone bodies (byproducts of fats) due to the lack of carbohydrates which are needed to metabolize fat. Fluids are also restricted during the diet. The beneficial effects of the ketogenic diet have been related to the induced state of ketosis, to dehydration, or to changes in salt disposition. A high incidence of urolithiasis (urinary tract stones) was observed in a group of 120 children who were on ketogenic diets for seizure control. Urolithiasis has been infrequently reported as a side effect of such diets. The medical records of the children were evaluated to identify any factors related to kidney stone development. The six children were aged one to eight years, and half were female. Stone fragments from four children were available. Urolithiasis developed from 1 to 30 months after start of the diet and one child had a family history of calcium kidney stones. Blood levels of uric acid and calcium were normal in four patients, as were urinary calcium levels, while four children had elevated blood creatinine levels, indicative of kidney dysfunction. Two children had elevated urinary levels of a salt, oxalate. Three patients had stones of uric acid, while another had calcium-containing stones. During ketosis, body fluids such as urine become acidic, and this likely led to decreased solubility of uric acid, leading to development of uric acid stones. Fluid restriction would also enhance this tendency. Possibly, calcium stones may have developed following intermittent elevation of urinary calcium levels. The study suggests that high levels of ketones in urine as well as acidic urine and fluid restriction facilitate kidney stone development. Periodic screening of urinary calcium levels is recommended as well as checking for blood in the urine, a sign of urolithiasis. (Consumer Summary produced by Reliance Medical Information, Inc.)

This study used validated questionnaires to assess patient perceptions regarding sexual function, urinary continence, and quality of life among women with bladder exstrophy and pelvic organ prolapse, with the conclusion that pelvic organ prolapse poses significant reductions in quality of life for women born with exstrophy, with effects on urinary continence and sexual function, and that identification and correction of prolapse appears to result in notable improvements in the lives of these patients.

Prior literature has documented the histological characteristics and surgical outcomes of classic bladder exstrophy (CBE) patients with polyps, but there has been no documentation about the histology of cloacal exstrophy (CE) polyps. CE is a rare entity with an incidence of 1:400,000 live births and having a CE patient with polyps is an additional rarity [1,2]. With the scarcity of research on CE patients with polyps, the goal of this study is to describe the removal of CE polyps during bladder closure and to investigate polyp histology. Five patients were included in the current case series. They were treated at the authors' institution between 1999 and 2010. All had a successful initial bladder closure and had their polyps removed at the time of closure. The average age of primary bladder closure was 20.4 months. Only one patient had recurrent polyps following initial polyp removal, and the recurrent polyps were removed during a subsequent bladder stone procedure. The histologic characteristics of polyps in this series were heterogeneous.

•We report on a case of an intussuscepted Meckel's diverticulum in a post-operative bladder exstrophy patient.•Slow return of bowel function in a patient with bladder exstrophy should prompt consideration of uncommon causes.•The relationship between bladder exstrophy and Meckel's diverticulum remains unknown.

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Mouse embryoid bodies (EBs) differentiate into dorsal spinal cord neural progenitors in response to retinoic acid (RA). Our data demonstrate that the addition of Sonic Hedgehog (Shh) directs towards a ventral spinal cord neural tube fate, but only at extremely high concentrations. One possible explanation is the presence of dorsal directing factors. Bone morphogenetic proteins (BMPs), known to direct dorsal spinal cord neural differentiation, were expressed in RA-treated EBs. Shh more potently directed ventral differentiation when combined with the BMP inhibitor Noggin. Further, when BMP7 was added, the ability of Shh to direct ventral differentiation was further mitigated.

In recent years, traditional views regarding the management of infants with intersex conditions have been challenged. Some of these patients have gender dysphoria and gender conversion, although most adults with intersex consider themselves to be either male or female. Hormonal and genetic factors may have a more important role in gender identity and sexual satisfaction than previously recognized, whereas the importance of phallus size to male gender identity and sexual satisfaction may have been overestimated. The impact of androgen imprinting on the developing brain is uncertain, but it is likely to be significant. The issue of genital surgery in infancy is controversial, although many adult patients concur that infancy is the best time for such procedures. Several reports indicate that the functional outcomes of genital surgery are poor, although more recently developed surgical techniques may achieve better results. Good communication between physicians, patients, and families regarding intersex conditions is paramount. We review current understanding of the evaluation and management of intersex conditions.

Successful initial surgical management of bladder exstrophy does not always lead to continence. We evaluated the ultrastructure of the exstrophic bladder using electron microscopy (EM) at various stages of reconstruction to determine whether morphology could correlate with the potential for continence.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in increased adrenal androgen secretion. When the deficiency is severe, the result is the salt losing (SL) form, and when the deficiency is partial, the result is the simple virilizing (SV) form of CAH. We documented long-term satisfaction with gender, cosmetic appearance and function of the genitalia, and surgical management practices in a group of women with CAH due to 21-hydroxylase deficiency.

We provide a 3-dimensional (3D) model of the pelvic floor musculature in patients with classic bladder exstrophy using magnetic resonance imaging (MRI).

Stone formation following bladder or continent reservoir reconstruction in children is a major source of long-term morbidity. We determine whether the method of stone removal (fragmentation or intact extraction) affected the time to stone recurrence in children after bladder reconstruction.

The objective of this study was to examine the complications associated with the orthopedic management of bladder exstrophy. The records of all patients seen for bladder exstrophy repair at the authors' institution between 1988 and 2002 were examined. Orthopedic complications were found to have occurred in 26 of 624 patients, yielding a complication rate of 4. The observed complications were divided into five categories bony complications at the osteotomy site, neurologic complications at the osteotomy site, complications of traction, deep infection, and late infections of the plate. Five of the 26 (19.2) complications were bony and involved non-union, delayed union, joint pain, or leg length inequality stemming from the osteotomy. Thirteen of the 26 (50) were neurologic complications. Four of the 26 (15.4) resulted from traction. All were due to tight dressing around the legs following surgery. Two of the 26 (7.7) were early deep infection and of the 26 (7.7) were late infections. This study highlights many of the complications associated with the management of exstrophy and provides suggestions on how to minimize them.

The use of continent urinary reservoirs has gained wide acceptance, particularly in urinary reconstruction in children with a small capacity or neuropathic bladder. When augmentation cystoplasty is combined with clean intermittent catheterization, patients are often able to achieve continence with low intravesical filling pressures and renal preservation. Often this approach requires fashioning a continent cutaneous stoma, which remains the most challenging aspect of continent urinary reservoirs. We analyzed our experience with continent diversion in patients with exstrophy-epispadias to determine complications and long-term results.

The cloacal-bladder exstrophy-epispadias complex represents a collection of congenital malformations caused by failed mesenchymal development during the first trimester. We sought to determine whether the exstrophy-epispadias complex is overrepresented among children conceived by in vitro fertilization (IVF).

Exposure to the phytoestrogen genistein (Indofine Chemical Co., Somerville, New Jersey) can disrupt normal male sexual differentiation. To determine if perinatal (that is gestation and lactation) genistein exposure at doses common in human diets alters masculinization we examined the development of the external genitalia, testes, wolffian ducts and sexual behavior in male rats exposed to genistein supplemented diets during early development.

Bladder exstrophy is a rare malformation affecting only 1 female out of every 5 patients. In the female initial closure is combined with reconstruction of the outer genitalia, and urinary continence can be achieved by some girls without the need for later bladder neck reconstruction. We evaluated the management and outcome of failed initial closures in the female exstrophy population.

Urinary continence is one of the primary goals in the surgical treatment of the patient with exstrophy. Children with inadequate bladder capacity, noncompliant or neuropathic bladder, or failed bladder neck reconstruction may require creation of a continent urinary reservoir to achieve continence. While initial success rates are excellent, some patients suffer persistent urinary incontinence, severely affecting their quality of life. The reasons for such failure and subsequent management were evaluated.

During early pregnancy, intermediate (extravillous) trophoblast infiltrates the basal plate and invades the spiral arteries, a physiological process required to establish the maternal–fetal circulation. Immunostaining studies have shown that differentiation of trophoblast into this invasive subpopulation is associated with down-regulation of E-cadherin expression. To study the function of E-cadherin in trophoblast in vitro, we restored E-cadherin expression in an E-cadherin negative human implantation site intermediate trophoblastic cell line, IST-1, using a recombinant adenovirus, E-cad/Ad5 which constitutively expresses E-cadherin. In contrast to the control IST-1 cells which were individual and pleomorphic in shape, E-cad/Ad5 transduced cells were cohesive, uniform, and round. The motility and invasiveness of E-cad/Ad5 transduced IST-1 cells, as compared with the control cells, was significantly reduced. These effects were contact-dependent and were attenuated by a function-perturbing anti-E-cadherin antibody. In conclusion, our results indicate that expression of E-cadherin in IST-1 cells results in a contact-mediated inhibition of motility and invasion and suggest an important role for E-cadherin down-regulation in the intermediate trophoblast during implantation.

Background: Although the immunologic effects of endogenous and synthetic estrogens are well studied, few studies have examined the hormonal effects of phytoestrogens (i.e., plant-derived estrogens) on the immune system. The primary goal of this study was to compare the effects of perinatal exposure with life-long exposure to genistein, an estrogenic compound in soy, on the endocrine and immune system in adulthood. Materials and Methods: Pregnant female rats were exposed to no, low (5 mg/kg diet), or high (300 mg/kg diet) genistein diets throughout gestation and lactation. At weaning, male offspring exposed to genistein perinatally were either switched to the genistein-free diet or remained on the genistein-dosed diets. At 70 days of age, immune organ masses, lymphocyte subpopulations, cytokine concentrations, and testosterone concentrations were assessed in male offspring. Results: Data were analyzed based on the diets that males were exposed to during gestation and lactation because life-long exposure to genistein had no additional effect on any of the dependent measures. Relative thymus masses were greater among males exposed to the high genistein diet than among males exposed to no genistein. Although the proportions of splenic and thymic CD4+T cells were not altered by genistein, the percentages of CD4+CD8+thymocytes, CD8+splenocytes, and total T cells in the spleen were higher and the percentages of CD4−CD8−thymocytes were lower among males exposed to genistein than among males not exposed to genistein. Synthesis of interferon-γ(IFN-γ) was marginally higher and testosterone concentrations were lower among genistein-exposed than genisteinfree males. Discussion: These data illustrate that exposure to genistein during pregnancy and lactation exerts long-lasting effects on the endocrine and immune systems in adulthood. Whether exposure to phytoestrogens during early development affects responses to infectious or autoimmune diseases, as well as cancers, later in life requires investigation.

Background/Purpose:The use of sigmoid colon segments to repair congenital deformities of the vagina is well established. There are little data, however, on complications or functional results in these patients. The purpose of this study was to evaluate complication rates and long-term patient outcomes in the use of sigmoid segments in vaginal reconstruction for congenital anomalies. Methods:The authors identified 28 patients who underwent vaginal reconstruction with sigmoid colon segments between 1985 and 2000 at their institution. Patient charts were reviewed for surgical technique, complication rates, cosmetic results, functional results, and psychosocial development. Patients were recalled for physical examinations and personal interviews to assess current status. Results:Of the 28 patients, 13 had male pseudohermaphroditism, 6 had Mayer-Rokitansky-Kuster-Hauser syndrome, 2 had true hermaphroditism, 2 had mixed gonadal dysgenesis, 2 had common urogenital sinus syndrome, 2 had adrenogenital syndrome, and 1 had penile agenesis. Mean patient age was 16 years (range, 6 to 21 years). Mean follow-up was 6.2 years (range, 2 months to 15 years). Postoperative complications included introital stenosis (4 patients), mucosal prolapse (4), partial small bowel obstruction (2), perineal wound hematoma (2), superficial wound infection (2), and vaginal prolapse (1). None of the complications have affected long-term patency or cosmesis of the neovagina, nor has mucous production significantly affected quality of life. Fourteen of 16 (88%) adult patients are heterosexually active, 1 is homosexually active, and 1 is asexual. Of the 14 heterosexually active patients, 11 (79%) are “very satisfied” with their psychosexual development and 3 are “comfortable.” Four patients are married, and 1 has carried a child to term. All adult patients felt that the appropriate time to undergo surgery was in adolescence. Conclusions:Reconstruction with sigmoid segments is an effective approach for many congenital conditions requiring vaginal reconstruction. Although surgical outcomes are not perfect, appropriately timed reconstructive vaginal surgery can provide most patients with an improved quality of life. For the best long-term results, a multidisciplinary team must be available from infancy to supply comprehensive support. J Pediatr Surg 37:629-633. Copyright 2002, Elsevier Science (USA). All rights reserved.

The authors describe a staged approach for pelvic closure applied in preadolescents and adolescents with previously failed closure of cloacal exstrophy. Closure of the pelvis was performed in four patients, 11 to 16 years old, with history of previous closures for their cloacal exstrophy that had resulted in either dehiscence or severe disfigurement. They were treated with pelvic osteotomies and external fixation; three later underwent internal fixation of the pubic rami. Genitourinary reconstructions were performed with the final stage of pelvic ring closure. Genitourinary closure was successful in all four patients despite a recurrent pubic diastasis resulting from sacroiliac joint instability in the patient not receiving internal fixation. Staged closure of the pelvis with iliac osteotomies, external fixation, gradual correction, and subsequent internal fixation of the approximated pubic rami can facilitate soft tissue closure of preadolescents and adolescents with unacceptably closed cloacal exstrophy.

Objectives:to document long-term medical, surgical and psychosexual outcome of individuals with congenital micropenis (13 males, 5 females). Methods:Physical measurements from childhood were collected retrospectively from medical records and at adulthood by physical examination. An adult psychosexual assessment was conducted with a written questionnaire and oral discussion. Results:Adult penile length was below the normal mean in all men. Three women had vaginoplasty resulting in normal length. All men reported goodor fairerections but 50% were dissatisfied with their genitalia. Dissatisfaction with body image resulted from having a small penis (66%), inadequate body hair (50%), gynecomastia (33%) and youthful appearance (33%). Ten men were heterosexual, 1 homosexual and 2 bisexual. Among women, 4 (80%) were dissatisfied with their genitalia. Three women reported average libido with orgasm and were also heterosexual. Two women had no sexual interest or experience. Finally, males were masculine and females feminine in their gender-role identity, and both groups were satisfied with their sex of rearing. Conclusions:Regarding choice of gender, male sex of rearing can result in satisfactory genito-sexual function. Female gender can also result in success, however it requires extensive feminizing surgery.

We present the pelvic floor anatomy of the major pelvic floor musculature in classic bladder exstrophy, including the levator ani, obturator internus and obturator externus. By improving our knowledge of pelvic floor anatomy we hope to understand better the relationship of the pelvic floor to the bony anatomy as well as the role of osteotomy in changing pelvic floor anatomy to enhance urinary control after surgery.

The surgical approach to the small newborn exstrophy bladder inadequate for primary closure remains undetermined. Various methods for long-term management have been implemented. We evaluated our experience with late primary closure of the small exstrophied bladder template.

We studied the untreated pelvic deformity in 14 adult patients with bladder exstrophy to determine the relative hip-joint force and stress and their effects on the clinical status of the hip. Pelvic radiographs were used for biomechanical analysis to calculate joint force and joint stress (force/area) relative to partial body weight, which allowed comparison between patients and age-matched controls. IOWA hip ratings were used for clinical evaluation, and hips were scored radiographically for degenerative joint disease. The mean relative joint force and joint stress was significantly higher for exstrophy patients (p< 0.001). In addition, the mean distance from the body center to the center of the femoral head was significantly increased (p< 0.001) in bladder exstrophy patients. An increase in diastasis correlated with an approximate 30 increase in the distance from the center of the femoral head to the body midline. The mean distance from the greater trochanter to the femoral head center was significantly less (p< 0.02) and the center–edge angle was significantly decreased in exstrophy patients (p< 0.05). Two patients' hips showed significant subluxation, and one of these showed degenerative hip disease in association with poor IOWA and radiographic scores.The force and stress on the hip joint are increased in untreated adult bladder exstrophy patients. Further longitudinal study is indicated to validate these findings and to determine whether clinically important degenerative changes are occurring. This could affect treatment recommendations in childhood.

The purpose of this study was to determine if there is an increased incidence of hypospadias in male offspring conceived by in vitro fertilization (IVF).

The modern staged approach to bladder exstrophy reconstruction has undergone significant changes since it was first advocated by Jeffs and Cendron in the 1970s. Although varied surgical approaches have been tried in the bladder exstrophy condition, the staged approach to bladder exstrophy repair has withstood the test of time. Progress continues to be made in evaluating the outcome of older types of staged reconstruction, with continuing modification and improvements in the modern approach to staged reconstruction. This treatise will update the reader on recent advances in the treatment of bladder and cloacal exstrophy

The development of adequate bladder capacity is not ensured in all patients with bladder exstrophy despite successful bladder closure and reconstruction. To determine the factors leading to the development and maturation of the exstrophic bladder we created a large animal model of exstrophy. We compared biopsies obtained from a cohort of experimentally induced exstrophic neonatal sheep bladders to those of normal control bladders and related the findings to a previously reported comparison of human neonatal normal and exstrophic bladders.

PurposeWe describe a staged approach for pelvic closure in patients with cloacal exstrophy, and evaluate the technique for functional and cosmetic results.Materials and MethodsStaged closure of the pelvis was performed in 5 patients 12 months to 14 years old with cloacal exstrophy at our institution, including some referred with a history of failed closure. The technique involves initial pelvic osteotomy followed by soft tissue and pelvic ring closure 2 to 3 weeks later. Clinical information is reviewed to assess the effectiveness of the technique.ResultsAt a mean followup of 3.2 years (range 1 to 9) closure was successful in all 5 patients without technical problems or surgical complications, and with excellent functional and cosmetic results.ConclusionsThis technique of staged pelvic closure may provide reliable initial or secondary repair in patients with cloacal exstrophy in whom 1-stage pelvic closure is unfeasible even with pelvic osteotomy.

PurposeExstrophy of the cloaca is a multisystem anomaly involving the gastrointestinal, nervous, musculoskeletal and genitourinary tracts which should be managed with a multidisciplinary approach. Improvement in management has led to survival for the majority of infants, and the focus has shifted to improvement in quality of life. The experience with management of cloacal exstrophy at a large center is evaluated.Materials and MethodsDemographic data as well as functional results of management of the multiple anomalies in 37 patients with cloacal exstrophy were evaluated. Surgical reconstruction was aimed at providing the best functional and cosmetic results.ResultsAverage patient age at review was 13.6 years. Most patients (32 of 37) had undergone an initial attempt at bladder closure from birth to greater than 24 months of age. Colostomy was performed when possible and if initial ileostomy was performed, the bowel was augmented later with the hindgut segment. When the hindgut segment was not used for bowel reconstruction, it was preserved for bladder augmentation or genital reconstruction. While urinary continence was achievable in many children, it was usually after augmentation and/or continent diversion.ConclusionsImprovements in perinatal management have increased survival in cloacal exstrophy. Therefore, the focus of reconstruction has shifted to reduction in the numbers of incontinent stomas, assistance with ambulation and improved cosmesis. All of these goals are achievable using a multidisciplinary approach to the management of this complex anomaly.

PurposeWe assessed the impact of posterior urethral obstruction after primary bladder exstrophy closure.Materials and MethodsA review of the records of patients with classic bladder exstrophy at our institution identified 29 boys and 12 girls with a mean age of 11.75 years who had had posterior urethral outlet obstruction after closure was done in the neonatal period.ResultsOf these 41 patients 75% underwent closure elsewhere. At closure osteotomies were done in 13 patients and 23 were younger than 72 hours. Paraextrophy skin flaps were used at primary closure in 27 cases (66%). Obstruction presented as recurrent urinary tract infection, upper tract deterioration with or without renal failure, bladder stones, difficult catheterization, urethral stitch erosion, a full bladder on ultrasound, a prolonged dry interval, urinary retention, inability to catheterize, bladder rupture, rectal prolapse and epididymitis or prostatitis. Usually the initial obstructive episode developed within 60 days of closure and it was recurrent. Therapy included suprapubic catheter placement, vesicostomy, ureterostomy, nephrostomy and multiple urethral manipulations, such as dilation with or without steroid injection, internal urethrotomy, urethral stitch removal, clean intermittent catheterization or open urethroplasty. All 6 patients who underwent long-term diversion via vesicostomy, ureterostomy or a conduit for greater than 6 months required permanent bowel segments for reconstruction, while in 5 of the 6 who underwent short-term diversion via nephrostomy or suprapubic tube placement for less than 6 months reconstruction was bowel-free. Of the 36 children in whom functional reconstruction was performed 9 are undergoing staged reconstruction, reconstruction failed in 14, 4 are socially dry and 9 are continent.ConclusionsPosterior urethral obstruction after exstrophy closure markedly decreases the success of staged bladder reconstruction, presents a significant risk to the upper urinary tract and should be detected early.

The bony pelvis was analyzed in 12 patients undergoing a further operation after initial bladder closure. Of the patients 5 had undergone a prior posterior osteotomy. All patients had wide diastasis of the pubis (average 5.5 cm.). In 9 of these patients late closure or reclosure of a failed initial bladder repair was done and 3 underwent a repeat bladder neck reconstruction. In all patients a new procedure, anterior iliac osteotomy with internal or external fixation, was performed. This procedure provides increased mobility of the pubis and increased correction. It avoids turning of the patient while under anesthesia for repeat preparation and in most cases postoperative traction is not needed. There were no instances of dehiscence, nonunion or infection. Three cases of transient femoral palsy were noted. All patients had a normal gait 4 months postoperatively.

• Bladder exstrophy is a congenital anomaly that has been difficult to correct. Advances in reconstructive surgery, some of which have originated at The Johns Hopkins Hospital, Baltimore, Md, have impacted on the care of these patients. We reviewed the progress made in patient care and the results of state-of-the-art treatment.(AJDC. 1989;143:1475-1478)

• A study was conducted in boys with bilateral cryptorchidism, who were to undergo surgical orchiopexy, to determine if target-organ androgen insensitivity might play a role in the failure of the testes to descend into the scrotum. Nine boys older than 1 year in whom bilateral undescended testes was the only genitourinary abnormality were evaluated. Each subject was administered a six-week course of human chorionic gonadotropin (hCG), 3000 U/m2 of body surface area, intramuscularly injected daily for five days and then twice per week. Basal and hCG-stimulated levels of testosterone were normal. However, hCG administration failed to induce testicular descent in all cases. At the time of surgery, scrotal skin and testicular biopsy specimens were obtained for propagation of cells in tissue culture. Androgen receptor levels and binding affinity were normal for the androgen-specific ligands dihydrotestosterone and metribolone in both skin fibroblasts and testicular cells. In addition, 5α-reductase activity was normal in scrotal skin fibroblasts. Nine boys with bilateral cryptorchidism and normal testicular androgen biosynthesis had normal androgen receptor-binding activity and 5α-reductase activity in cultured scrotal skin fibroblasts and testicular cells. Therefore, bilateral maldescent of the testes in these boys with cryptorchidism was not due to androgen insensitivity.(AJDC 1988;142:933-936)

A quantitative histological study of the dilated ureter of childhood was performed on 26 ureters. The specimens were from 15 male and 11 female patients 10 days to 12 years old (mean age 2.0 years). A color image analysis system was used to examine and compare collagen and smooth muscle components of the muscularis layers to normal control ureters of similar age. In comparing primary obstructed (12) to primary refluxing (14) megaureters and control ureters (6), there was a statistically different collagen-to-smooth muscle ratio (p <0.001) between the primary obstructed and primary refluxing megaureter groups. For patients with primary refluxing megaureter there was a 2-fold increase in the tissue matrix ratio of collagen-to-smooth muscle when compared to patients with primary obstructed megaureter. In the primary obstructed megaureters the amount of collagen and smooth muscle was not statistically different from controls (p >0.01). The increased tissue matrix ratio of 2.0 ± 0.35 (collagen-to-smooth muscle) in the refluxing megaureter group compared to 0.78 ± 0.22 in the obstructed megaureter group and 0.52 ± 0.12 in controls was found to be due not only to a marked increase in collagen but also a significant decrease in the smooth muscle component of the tissue. Primary obstructed and normal control ureters had similar quantitative amounts of smooth muscle with 60 ± 5% and 61 ± 6%, respectively, while refluxing megaureters had only 40 ± 5% smooth muscle. The percentage collagen was 36 ± 5 in the obstructed megaureter group and 30 ± 5 in controls, with refluxing megaureters having 58 ± 5% collagen on analysis. Our findings emphasize the significant differences in the structural components (collagen and smooth muscle) of the dilated ureter of childhood, and provide us with further insight into the pathological nature of these dilated ureters and their surgical repair.

An analysis of the potential of recombinant human tumor necrosis factor to enhance the radiosensitivity of C1300 murine neuroblastoma was undertaken. Female A/J mice bearing C1300 murine neuroblastoma (right hindlimb) underwent the following treatments: group 1—0.25 cc normal saline intraperitoneally times 2, group 2—0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2, group 3—400 cGy. right hindlimb, group 4—800 cGy. right hindlimb, group 5—400 cGy. right hindlimb plus 0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2 and group 6—800 cGy. right hindlimb plus 0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2. All animals were followed for 21 days after treatment initiation with interval measurements of tumor volume. All single modality treatments were more effective than normal saline in reducing average tumor volumes during the study period (800 cGy. equals recombinant human tumor necrosis factor greater than 400 cGy. greater than normal saline). The addition of recombinant human tumor necrosis factor to radiotherapy moderately augmented antitumor response at radiation doses of 400 cGy. but marked enhancement was attained at radiation doses of 800 cGy. (p <0.02). This enhancement was achieved without increased animal morbidity or mortality. Animals receiving recombinant human tumor necrosis factor in addition to 800 cGy. demonstrated increased survival when compared with animals receiving 800 cGy. alone (p <0.02). Although statistical synergy was not proved, recombinant human tumor necrosis factor appears to augment significantly radiation-induced tumor regression at no toxic cost to the animal.

There are two common electrophoretic variants (allozymes) of murine glucosephosphate isomerase (GPI). In order to develop immunocytochemical procedures that are allozyme-specific, the two variants (GPI-1A and GPI-1B) were purified from skeletal muscle of several mouse strains and used as antigens for the elicitation of antibodies. The allozymes were purified to a specific activity of 800 units/mg by substrate elution from cellulose phosphate. When the purified allozymes were presented as antigens to goats, rabbits, and mice (both syngeneically and allogeneically), the goats and rabbits produced high titers of anti-GPI antibody, but no humoral antibody was detected in the mice, as determined by radioimmunoassays. Antisera specific for the GPI-1B variant were enriched by absorbing selected sera with GPI-1A conjugated to Sepharose 4B. No antisera specific for GPI-1A were detected following the immunizations. The specificity of the anti-GPI-1B antisera provides a unique opportunity for the development of immunocytochemical procedures for studying the distribution of this allozyme in chimeric mouse tissues.

The enzyme glucosephosphate isomerase (GPI) is of interest because of its role in glycolysis and its use as a cell marker in studies of embryogenesis utilizing chimeras. The distribution of GPI was determined in histologic sections of ovarian follicles and the tissues of early embryonic stages of the mouse. Antibodies of GPI were combined in an immunocytochemical procedure utilizing peroxidase-antiperoxidase to localize GPI in tissue sections.During follicular maturation, GPI is first detected in oocytes of small follicles and then in the granulosa cells of slightly larger follicles. The relative concentrations of GPI remain high in the granulosa cells adjacent to the oocyte as the follicles mature. GPI in the granulosa cells may play a role in providing the growing oocyte with low molecular weight energy sources. Within the conceptus, differences in GPI concentrations among tissues become apparent during the formation of the egg cylinder. The highest concentrations of GPI are in the embryonic ectoderm, the amniotic folds, the extraembryonic ectoderm, and the ectoplacental cone. These are areas of intense mitotic activity. The energy required for cell divisions during embryogenesis is derived from glycolysis, thus the high concentrations of GPI in these tissues correlates well with the cellular function.

Of the 148 patients with bladder exstrophy seen at this institution during the last 10 years 12 have ultimately required bladder augmentation. In 4 cases augmentation was performed for an inadequate bladder capacity, upper tract decompensation and dry interval of less than 1 hour after bladder neck reconstruction and epispadias repair. Likewise, 3 patients underwent augmentation for an inadequate bladder capacity and dry interval of less than 2 hours after bladder neck reconstruction and epispadias repair. Of these 7 patients 3 had undergone 2 previous bladder neck reconstructions, while 4 had undergone 1 prior repair. Five augmentations were performed for an inadequate bladder capacity before any type of continence procedure had been done.

We have constructed cDNA libraries representing transcripts from purified populations of germ cells and of somatic cells, isolated from fetal mouse gonads at 12.5 days postcoitum (dpc). We have used these libraries to study differential gene expression in fetal germ cells on the basis of differential representation of specific cDNAs in each library. We show that in addition to expression of housekeeping genes at expected levels, four genes responsible for germ cell-specific phenotypes are expressed at significantly different levels in germ cells and surrounding somatic cells. These include tissue-nonspecific alkaline phosphatase (tnAP), transcription factor Oct-3/4, the c-kitproto-oncogene, and DNA methyltransferase (Mt). The significance of these results is discussed in the context of events contributing to early development of germ cells. It is concluded that fetal germ cells appear to retain a pattern of gene expression resembling that in early pluripotent embryonic cells, and that this may be important for the maintenance of genetic totipotency.

Gender assignment in the newborn with ambiguous genitalia poses a dilemma for the parents and physician, even if the infant has a normal 46XX or 46XY karyotype. In general, female pseudohermaphrodites are reared as female subjects, since they can undergo reconstruction to appear as phenotypic female subjects and they may even be able to bear children. Male pseudohermaphrodites, patients with mixed gonadal dysgenesis and male patients with a micropenis may not be so straightforward, and proper gender assignment in these infants may be difficult.

From November 1986 through May 1989, a Food and Drug Administration approved investigational study was done to assess the safety and efficacy of glutaraldehyde cross-linked bovine dermal collagen in the endoscopic treatment of vesicoureteral reflux. Over-all, 57 patients (92 ureters) were treated. The majority of ureters (68.5%) had grade II to III/V vesicoureteral reflux (international classification). One treatment was given in 61.4% of the patients, while 33.3% required 2 and 5.3% required 3 treatments. Nonduplicated/primarily refluxing ureters comprised 68.5% of the total, while 13% were duplex/primarily refluxing and 18.5% were surgical failures. The procedures were performed on an outpatient basis in all but 3 patients. Patients were evaluated by voiding cystourethrogram and renal/bladder sonography before and after treatment at 1 month and 1 year. Cure at 1 month after the last treatment was achieved in 75% of the ureters. Among the ureters cured at 1 month the cure persisted in 79% at 1 year after treatment. Cure at 1 year was achieved in 65% of all ureters evaluated, regardless of the status at 1 month. Procedure-related morbidity was minimal and there were no adverse reactions to the implant substance. Thus, glutaraldehyde cross-linked bovine dermal collagen appears to be safe and effective in the endoscopic treatment of vesicoureteral reflux.

We reviewed the cases of the exstrophy/epispadias complex treated at our institution between July 1976 and April 1992. A total of 78 patients was identified who had paraexstrophy skin flaps used in the bladder closure, of whom 31 (40%) had a complication as a result of the flaps. The main complication encountered was a urethral stricture where the paraexstrophy skin flaps joined the urethral plate area. Multiple maneuvers were undertaken to correct these problems, including direct vision internal urethrotomy (12 cases), multiple urethral dilations (4), open revision (3) and full thickness skin grafts (5). Seven patients had such a complex stricture situation that they required either continent urinary diversion (5), colon conduit diversion (1) or cutaneous ureterostomy (1), the latter 2 patients having undergone vesicostomy elsewhere before referral. Of the remaining 24 patients who did not undergo a diversionary procedure 12 have undergone an epispadias repair and bladder neck reconstruction, 7 underwent an epispadias repair and 5 await further treatment.

While female epispadias is a rare congenital anomaly, the treatment of complete epispadias in the female patient does not significantly differ from that of their male counterparts, although the female defect can be overlooked as a cause of incontinence. Attention must be given to the creation of an adequate urethral channel so that an adequate bladder capacity can be achieved and eventual bladder neck plasty can be performed. Finally, attention must be given to the reconstruction of the external genital defect. During the last 7 years 11 female patients with complete epispadias were treated. Of these patients 4 were referred from elsewhere and 3 had failed a previous procedure (2 had recently undergone external genital and urethral reconstruction, 1 underwent urinary diversion after multiple failed bladder neck procedures). Nine patients underwent bladder neck plasty: 5 are completely continent day and night, 3 are dry for greater than 3hours during the day, and 1 is dry for only 1 to 3hours during the day and wet at night, for an overall continence rate of 87.5%. Our experience with these patients has taught us that the bladder in this condition is much like that found in complete male epispadias. Therefore, creating a urethral outlet with sufficient length and resistance along with simultaneous reconstruction of the external genitalia allows for bladder regrowth, thus, facilitating achievement of greater volumes and bladder neck reconstruction with an excellent chance of success.