Faculty Bibliography

PURPOSE: We determine whether smooth and skeletal muscle or nerve density is altered in the lower genitourinary or gastrointestinal tract of male human fetuses with myelomeningocele at 20 weeks of gestation. MATERIALS AND METHODS: We serially cross sectioned the lower genitourinary and gastrointestinal tracts in 7 male fetuses (mean age 20 weeks of gestation) with myelomeningocele and 4 age matched controls. Immunohistochemical staining was performed using Masson's trichrome stain and antibodies to smooth and skeletal muscle actin. S-100 protein staining for Schwann cell localization and neurofilament protein was also done. Fluorescein and rhodamine double immunolabeling was used to demonstrate the co-expression of smooth and skeletal muscle. RESULTS: Peripheral neural innervation of the bladder, prostate and rectum was markedly decreased in myelomeningocele. Masson's trichrome and smooth muscle actin staining also demonstrated that smooth muscle was less well differentiated in myelomeningocele specimens. Scant smooth muscle was present in the myelomeningocele bladder and bladder neck with an excess of collagen in an interfascicular and intrafascicular distribution. Double immunofluorescence staining revealed persistent co-expression of smooth and skeletal muscle actin by myocytes in the myelomeningocele detrusor, while in the control bladder there was only smooth muscle expression. The skeletal muscle component of structures in fetuses with myelomeningocele, including the external sphincter, was similar to that in controls. Prostatic size, ductal morphogenesis and smooth muscle were decreased compared to those in controls. CONCLUSIONS: A global defect exists in the development of smooth muscle in myelomeningocele in the lower genitourinary and gastrointestinal tracts by 20 weeks of gestation. Peripheral nerve density is decreased in smooth muscle in myelomeningocele, suggesting that an intact nervous system is important for the development of normal smooth muscle. Fetal surgery with coverage of the spinal cord in select cases may prevent progressive environmental injury to the somatic nervous system during the second half of gestation. However, achieving normal autonomic function is unlikely due to the extent of early global organ maldevelopment

PURPOSE: To evaluate the contractile effect of endothelin-1 (ET-1) on prostatic urethral pressure and to characterize the effect of the selective ETA receptor antagonist PD155080 on ET-1 mediated prostatic urethral pressure. MATERIALS AND METHODS: The effect of intravenous ET-1 administration on canine urethral pressure was determined in the presence and absence of PD155080. The affinity of PD155080 for endothelin-mediated contraction was determined using antagonist dissociation studies. Saturation and competition binding studies were performed using [125I] ET-1 in both human and canine prostate. RESULTS: ET-1 bolus injection elicited shallow and prolonged increases the prostatic urethral pressure. Pretreatment with PD155080 totally abolished the urethral contractile response to ET-1. Specific [125I] ET-1 binding was saturable and of high affinity. Two ET receptor subtypes (ETA receptor, ETB receptor) have been identified in human prostate. The ratio of ETA to ETB receptors was approximately 1.5:1 in both human and canine prostates. Isometric tension studies revealed that PD155080 shifted the ET-1 dose-response curves to the right and exhibited no effect on the ETB receptor selective agonist sarafotoxin dose-response curves. CONCLUSION: ET-1 mediates prostate smooth muscle tone and may play a role in the pathophysiology and treatment of benign prostatic hyperplasia (BPH)

BACKGROUND: Although quantitative morphometry of benign prostatic hyperplasia (BPH) has been described, there is a paucity of information on the morphometry of the nonhyperplastic prostate. This study determines the histologic composition of prostates obtained from males, ages 2 days to 40 years, in order to provide insights into the morphometry of the 'normal' gland. METHODS: The histologic composition of 45 prostates was obtained from autopsies of males with age groups stratified to reflect the neonatal, childhood, peripubertal, adolescent, and young adult periods. Double immunoenzymatic staining and computer image analysis were used to determine the mean area densities of the smooth muscle (SM), connective tissue (CT), glandular epithelium (E), and lumen (L). RESULTS: A progressive decrease in SM area density throughout childhood, prepuberty, and puberty was seen. The density of SM significantly increased following puberty and throughout adolescence and early adulthood. There was a concomitant increase in CT from the neonatal period throughout childhood, prepuberty, and puberty, and a decrease after puberty and throughout adolescence and early adulthood. Since the changes in SM and CT were inversely related, the percent contribution of the stromal compartment to the total gland remained constant. CONCLUSIONS: The stromal to epithelial ratio remains constant from birth to age 40 in nonhyperplastic glands and is similar to the ratios in asymptomatic and symptomatic BPH tissues

Vaginal bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia and has been proposed to be due to a treatment-induced activation of the hypothalamic-pituitary-ovarian axis. We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation. The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant's hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy

PURPOSE: To characterize the functional effect of endothelin-1 (ET1) and endothelin-3 (ET3), immunohistochemically localize ET1-like immunoreactivity, and measure the tissue levels of immunoreactive endothelin (irET) in canine genitourinary (GU) tissues. MATERIALS AND METHODS: Canine GU tissues were characterized by measuring ET1 levels using a RIA, immunohistochemical staining of ET1 and isometric tension studies. RESULTS: Immunoreactive endothelin was present, to varying degrees, in the vas deferens, ureter, prostate, bladder and urethra. Functionally, ET1 demonstrated the typical concentration response characteristics in the canine bladder base, bladder body, and prostate. The maximal tension (Emax) measured following ET1 challenge was approximately 20-fold greater in the bladder body (0.67 +/- 0.21 g/mm.2) and bladder base (0.48 +/- 0.18 g/mm.2) as compared to the prostate 0.04 +/- 0.001 g/mm.2 The Emax of ET3 in the bladder body (0.31 +/- 0.12 g/mm.2) and bladder base (0.19 +/- 0.08 g/mm.2) was significantly lower than the corresponding Emax of ET1. No measurable contractile response was elicited by ET3 in the canine prostate. Immunohistochemical staining localized the ET-like immunoreactivity to the glandular epithelium of the prostate and the transitional epithelium of the bladder. CONCLUSIONS: Endothelins are ubiquitous in the canine lower GU tract with predominant localization to the epithelial elements. Endothelins are also functionally active in canine GU tissues, but the specific role of endothelins in the physiology and pathophysiology of GU tissues requires further investigation

OBJECTIVES: To evaluate changes in the smooth muscle and connective tissue development in the obstructed and normal fetal bladder. METHODS: The smooth muscle and connective tissue composition of 19 fetal urinary bladders, including those of 9 fetuses with anatomic obstruction and 10 controls free of urologic disease, were analyzed by light microscopy and computer-assisted color image analysis. RESULTS: The bladder wall thickness was markedly increased in obstructed fetuses throughout gestation as compared with that in controls. The disparity in bladder wall thickness increased rapidly during gestation. The percent area density of smooth muscle and connective tissue as well as the ratio of smooth muscle to connective tissue remained the same in the obstructed and normal control fetal bladders. CONCLUSIONS: Although bladder outlet obstruction is associated with a marked increase in bladder wall thickness, the percent of smooth muscle and connective tissue comprising the mural histology remains relatively constant as compared with that of normal fetal controls. This study suggests that bladder outlet obstruction in the fetus is not associated with excess collagen deposition but rather with an increased amount of bladder with normal cellular content and a concomitant increase in smooth muscle development

PURPOSE: We demonstrated survival and expansion in vivo of urothelial free autografts on demucosalized seromuscular segments. MATERIALS AND METHODS: Four methods of in vivo urothelial expansion were investigated on demucosalized colonic segments in the canine model. Group 1 underwent colonic mucosal removal by manual stripping, group 2 underwent removal of colonic mucosa and submucosa, and group 3 underwent manual stripping of the colonic mucosa followed by treatment with protamine sulfate and urea. In the 3 groups urothelial autografts were then placed on the seromuscular segment and tubularized over a balloon splint. In group 4 the colonic mucosa was removed but the grafts were not tubularized. Instead the colonic segment was sutured to the parietal peritoneum. RESULTS: Group 4 grafts had no epithelial growth and shrinkage of the bowel segment. Group 1 grafts had minimal growth with no expansion and colonic mucosal regrowth. Group 2 grafts demonstrated growth and expansion, although these colonic segments had a significant inflammatory response and fibrosis. Group 3 grafts had the best growth and expansion with the least inflammatory response, and 1 colonic segment was almost completely covered with urothelium. CONCLUSIONS: We demonstrated in vivo expansion of urothelial autografts grown on seromuscular colonic segments. Preservation of the submucosa is essential to prevent fibrosis of the seromuscular colonic segment and a balloon stent is crucial to prevent graft contraction. Treatment of the demucosalized segment with protamine sulfate and urea results in better urothelial expansion and less colonic mucosal regrowth

OBJECTIVES. To compare the cellular composition of benign prostatic hyperplasia (BPH) in Chinese and Caucasian-American men. METHODS. Surgical specimens of the prostate were obtained from 9 Chinese and 8 Caucasian-American men undergoing cystoprostatectomy for invasive transitional cell carcinoma. The mean ages of the Chinese and Caucasian-American men were 66.8 years and 66.4 years, respectively (P = 0.94). The mean prostate weight of the Chinese and Caucasian-American men was 53.4 g and 32.1 g, respectively (P = 0.01). Double immunoenzymatic staining with antibodies against actin and prostatic acid phosphatase and computer-assisted color image analysis were performed on whole-mount tissue sections. The percent area density of smooth muscle (SM), connective tissue (CT), epithelium (E), and epithelial lumen (L) were obtained by analyzing 30 fields from each specimen. RESULTS. The mean percent area density of SM, CT, E, and L in the prostate of Chinese men was 32%, 9.1%, 10.8%, and 48.5%, respectively. The mean percent area density of SM, CT, E, and L in the prostate of Caucasian-American men was 52.5%, 27.9%, 12.8%, and 7%, respectively. Overall, the prostates of Chinese men contained significantly more glandular lumen and significantly less SM and CT. CONCLUSIONS. The present study demonstrates that the cellular composition of BPH in the prostates of Caucasian-American and Chinese men is different. These cellular differences may account for previously observed differences in the incidence of clinical BPH