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Urologist, Pediatric Specialist
29 years of experience
Accepting new patients
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Credentials

Education ?

Medical School Score Rankings
University of California at Los Angeles (1983)
  •  
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Urinary Bladder Neck Obstruction
Patients' Choice Award (2015)
Compassionate Doctor Recognition (2015)
Associations
American Urological Association
American College of Surgeons
American Board of Urology

Affiliations ?

Dr. Zderic is affiliated with 3 hospitals.

Hospital Affiliations

Score

Rankings

  • Children's Hospital of Philadelphia
    324 S 34th St, Philadelphia, PA 19104
    •  
  • Hospital of the University of Pennsylvania
  • Chop Clinical Associates
  • Publications & Research

    Dr. Zderic has contributed to 100 publications.
    Title Transcriptional Repression of Caveolin-1 (cav1) Gene Expression by Gata-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings.
    Date August 2011
    Journal The American Journal of Pathology
    Excerpt

    Hypertrophy occurs in urinary bladder wall smooth muscle (BSM) in men with partial bladder outlet obstruction (PBOO) caused by benign prostatic hyperplasia (BPH) and in animal models of PBOO. Hypertrophied BSM from the rabbit model exhibits down-regulation of caveolin-1, a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. The proximal promoter of the human and mouse caveolin-1 (CAV1) gene was characterized, and it was observed that the transcription factor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and human beings. Silencing of GATA6 gene expression up-regulates caveolin-1 expression, whereas overexpression of GATA-6 protein sustains the transcriptional repression of caveolin-1 in bladder smooth muscle cells. Together, these data suggest that GATA-6 acts as a transcriptional repressor of CAV1 gene expression in PBOO-induced BSM hypertrophy in men and mice. GATA-6-induced transcriptional repression represents a new regulatory mechanism of CAV1 gene expression in pathologic BSM, and may serve as a target for new therapy for BPH-induced bladder dysfunction in aging men.

    Title Detrusor Overactivity is Associated with Downregulation of Large-conductance Calcium- and Voltage-activated Potassium Channel Protein.
    Date June 2010
    Journal American Journal of Physiology. Renal Physiology
    Excerpt

    Large-conductance voltage- and calcium-activated potassium (BK) channels have been shown to play a role in detrusor overactivity (DO). The goal of this study was to determine whether bladder outlet obstruction-induced DO is associated with downregulation of BK channels and whether BK channels affect myosin light chain 20 (MLC(20)) phosphorylation in detrusor smooth muscle (DSM). Partial bladder outlet obstruction (PBOO) was surgically induced in male New Zealand White rabbits. The rabbit PBOO model shows decreased voided volumes and increased voiding frequency. DSM from PBOO rabbits also show enhanced spontaneous contractions compared with control. Both BK channel alpha- and beta-subunits were significantly decreased in DSM from PBOO rabbits. Immunostaining shows BKbeta mainly expressed in DSM, and its expression is much less in PBOO DSM compared with control DSM. Furthermore, a translational study was performed to see whether the finding discovered in the animal model can be translated to human patients. The urodynamic study demonstrates several overactive DSM contractions during the urine-filling stage in benign prostatic hyperplasia (BPH) patients with DO, while DSM is very quiet in BPH patients without DO. DSM biopsies revealed significantly less BK channel expression at both mRNA and protein levels. The degree of downregulation of the BK beta-subunit was greater than that of the BK alpha-subunit, and the downregulation of BK was only associated with DO, not BPH. Finally, the small interference (si) RNA-mediated downregulation of the BK beta-subunit was employed to study the effect of BK depletion on MLC(20) phosphorylation. siRNA-mediated BK channel reduction was associated with an increased MLC(20) phosphorylation level in cultured DSM cells. In summary, PBOO-induced DO is associated with downregulation of BK channel expression in the rabbit model, and this finding can be translated to human BPH patients with DO. Furthermore, downregulation of the BK channel may contribute to DO by increasing the basal level of MLC(20) phosphorylation.

    Title Bilateral Pelvi-ureteric Junction Obstruction in a Neonate Presenting with Sudden Anuria.
    Date December 2009
    Journal Journal of Pediatric Urology
    Excerpt

    We report an extremely rare case of a female neonate with antenatally diagnosed bilateral moderate hydronephrosis and appropriate postnatal follow up who presented at 6 weeks of life with sudden onset of anuria secondary to bilateral pelvi-ureteric junction obstructions. While most antenatally diagnosed hydronephrosis remains asymptomatic, this case serves as a reminder that neonatal patients can become acutely symptomatic.

    Title Alterations in Caveolin Expression and Ultrastructure After Bladder Smooth Muscle Hypertrophy.
    Date October 2009
    Journal The Journal of Urology
    Excerpt

    Partial bladder outlet obstruction in male rabbits causes detrusor smooth muscle hypertrophy and voiding dysfunction similar to that observed in men with benign prostate hyperplasia. Using this model, we analyzed the protein expression and ultrastructure of caveolae and the intermediate size filament in detrusor smooth muscle following partial bladder outlet obstruction induced hypertrophy.

    Title Alteration of the Pkc-mediated Signaling Pathway for Smooth Muscle Contraction in Obstruction-induced Hypertrophy of the Urinary Bladder.
    Date July 2009
    Journal Laboratory Investigation; a Journal of Technical Methods and Pathology
    Excerpt

    Normal urinary bladder function requires contraction and relaxation of the detrusor smooth muscle (DSM). The DSM undergoes compensatory hypertrophy in response to partial bladder outlet obstruction (PBOO) in both men and animal models. Following bladder hypertrophy, the bladder either retains its normal function (compensated) or becomes dysfunctional (decompensated) with increased voiding frequency and decreased void volume. We analyzed the contractile characteristics of DSM in a rabbit model of PBOO. The protein kinase C (PKC) agonist phorbol 12, 13-dibutyrate (PDBu) elicited similar levels of contraction of DSM strips from normal and compensated bladders. However, PDBu-induced contraction decreased significantly in DSM strips from decompensated bladders. The expression and activity of PKC-alpha were also lowest in decompensated bladders. The PKC-specific inhibitor bisindolylmaleimide-1 (Bis) blocked PDBu-induced contraction and PKC activity in all three groups. Moreover, the phosphorylation of the phosphoprotein inhibitor CPI-17 (a 17-kDa PKC-potentiated inhibitory protein of protein phosphatase-1) was diminished in DSM from the decompensated bladder, which would result in less inhibitory potency of CPI-17 on myosin light chain phosphatase activity and contribute to less contractility. Immunostaining revealed the colocalization of PKC and phosphorylated CPI-17 in the DSM and confirmed the decreases of these signaling proteins in the decompensated bladder. Our results show a differential PKC-mediated DSM contraction with corresponding alterations of PKC expression, activity and the phosphorylation of CPI-17. Our finding suggests a significant correlation between bladder function and PKC pathway. An impaired PKC pathway appears to be correlated with severe bladder dysfunction observed in decompensated bladders.

    Title Quantifying Demographic, Urological and Behavioral Characteristics of Children with Lower Urinary Tract Symptoms.
    Date October 2008
    Journal Journal of Pediatric Urology
    Excerpt

    OBJECTIVE: This project examines the voiding and behavioral characteristics of children referred to a specialty voiding clinic, including the impact of incontinence on the child and family. PATIENTS AND METHODS: A total of 351 new patients (aged 5-17 years) referred to our specialty voiding clinic completed background information, including demographics and medical history, a standardized voiding questionnaire, school history, and questions about child and family quality of life, prior to their first appointment. RESULTS: Patients are primarily female (53%) and Caucasian (70%) with a mean age of 9.5 years (range 5-17; SD=3.5). Of the patients, 25% were diagnosed with a mental or behavioral health problem. Mean urological symptom score was 12 (range 0-29). Higher symptom scores are associated with younger age, ethnic minority status, a mental health diagnosis, being on psychotropic medications, and a poor child and family quality of life. Families of children who are wet day and night reported a poorer quality of life as compared to the families of children who were daytime wetters or bedwetters only. CONCLUSION: Symptom scores are associated with type of incontinence, social and quality of life variables. Collecting this baseline data will enable ongoing monitoring of progress for these complex patients.

    Title Impact of Overactive Bladder on the Brain: Central Sequelae of a Visceral Pathology.
    Date August 2008
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Neural circuits that allow for reciprocal communication between the brain and viscera are critical for coordinating behavior with visceral activity. At the same time, these circuits are positioned to convey signals from pathologic events occurring in viscera to the brain, thereby providing a structural basis for comorbid central and peripheral symptoms. In the pons, Barrington's nucleus and the norepinephrine (NE) nucleus, locus coeruleus (LC), are integral to a circuit that links the pelvic viscera with the forebrain and coordinates pelvic visceral activity with arousal and behavior. Here, we demonstrate that a prevalent bladder dysfunction, produced by partial obstruction in rat, has an enduring disruptive impact on cortical activity through this circuit. Within 2 weeks of partial bladder obstruction, the activity of LC neurons was tonically elevated. LC hyperactivity was associated with cortical electroencephalographic activation that was characterized by decreased low-frequency (1-3 Hz) activity and prominent theta oscillations (6-8 Hz) that persisted for 4 weeks. Selective lesion of the LC-NE system significantly attenuated the cortical effects. The findings underscore the potential for significant neurobehavioral consequences of bladder disorders, including hyperarousal, sleep disturbances, and disruption of sensorimotor integration, as a result of central noradrenergic hyperactivity. The results further imply that pharmacological manipulation of central NE function may alleviate central sequelae of these visceral disorders.

    Title Intracytoplasmic Sperm Injection (icsi) with Transmission of a Ring(y) Chromosome and Ovotesticular Disorder of Sex Development in Offspring.
    Date August 2008
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    We present a newborn infant with ovotesticular disorder of sex development and sex chromosome mosaicism with a supernumerary ring(Y), and a normal female cell line (47,XXr(Y)[10]/46,XX[40]. The ring (Y) was inherited from the child's father, and was transmitted following assisted reproductive technology and intracytoplasmic sperm injection (ICSI). The father presented with infertility and oligospermia, but cytogenetic analysis had not been carried out as part of the infertility workup. The Y containing cell line had not been seen on amniocentesis, which had shown a 46,XX apparently normal female karyotype in all cells studied. Molecular analysis using polymorphic probes from the X chromosome demonstrated that the 47,XXr(Y) cell line in the child was consistent with inheritance from the father, following meiosis I paternal non-disjunction. This report underscores the need to obtain chromosome analysis in couples with infertility who undergo assisted reproduction.

    Title Beta and Gamma-sarcoglycans Are Decreased in the Detrusor Smooth Muscle Cells of the Partially Obstructed Rabbit Bladder.
    Date May 2008
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We evaluated and quantified the levels of sarcoglycans present in the detrusor muscle layer of rabbits with partial bladder outlet obstruction. MATERIALS AND METHODS: Rabbits underwent surgery, as previously described, to partially obstruct the urethra. One, 3, 7 and 14 days after obstruction the detrusor muscle layer was dissected free of the remaining bladder tissue and extracted with detergent to isolate the transmembrane components of the dystroglycan-glycoprotein complex. Several components of the dystroglycan-glycoprotein complex were characterized and quantified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. RESULTS: Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis several bands were noted on gels with a molecular weight (43 and 35 kDa, respectively) corresponding to beta and gamma-sarcoglycan. As obstruction progressed longitudinally, the levels of beta and gamma-sarcoglycan showed progressive decrease at the protein level with beta-sarcoglycan levels recovering at later time points. Bladders with a functional physiology that showed more advanced symptoms of dysfunction had a greater decrease in beta and gamma-sarcoglycan protein. CONCLUSIONS: The levels of beta and gamma-sarcoglycan progressively change with obstruction with greater changes occurring in the levels of gamma-sarcoglycan. It is likely that alterations in the dystroglycan-glycoprotein complex are responsible for some of the changes in muscle physiology that occur as a consequence of obstruction.

    Title Deletion of One Serca2 Allele Confers Protection Against Bladder Wall Hypertrophy in a Murine Model of Partial Bladder Outlet Obstruction.
    Date February 2008
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    The sarco(endo)plasmic reticulum Ca(2+)-ATPase2 (SERCA2) is downregulated in cardiac hypertrophy with decompensation. We sought to determine whether mice heterozygous for the SERCA2 allele would develop greater bladder hypertrophy and decompensation than their wild-type littermates following partial bladder outlet obstruction (pBOO). We found that following 4 wk of surgically created pBOO, SERCA2 heterozygous murine bladders showed significantly less hypertrophy, improved in vitro cystometry performance, diminished expression of the slow myosin isoform A analyzed by RT-PCR, a significant drop in nuclear translocation of nuclear factor of activated T cells by EMSA, and decreased cell proliferation within the smooth muscle layer following 5-bromo-2'-deoxyuridine labeling compared with their wild-type littermates. Thus, in contrast to cardiac muscle, deletion of a SERCA2 allele confers protection against bladder hypertrophy in a murine model of pBOO. Compensatory mechanisms in heterozygous mice seem to be related to the calcineurin pathway. Further studies are underway to better define the molecular basis of this observation, which has potential clinical applications.

    Title Structural and Functional Characterization of Bladder Smooth Muscle in Fetal Rats with Retinoic Acid-induced Myelomeningocele.
    Date February 2007
    Journal American Journal of Physiology. Renal Physiology
    Excerpt

    Myelomeningocele (MMC) is the most common cause of neurogenic bladder dysfunction (NBD). We recently developed a novel retinoic acid (RA)-induced MMC model in fetal rats. The objective of this study was to use this model to assess functional and structural characteristics of the detrusor muscle in MMC-associated NBD. Time-dated pregnant Sprague-Dawley rats were gavage fed 60 mg/kg RA dissolved in olive oil or olive oil alone [embryonic day 10 (E10)]. Bladder specimens from olive oil-exposed fetuses (OIL; n = 71), MMC (n = 79), and RA-exposed-no MMC (RA, n = 62) were randomly assigned for functional and histopathological evaluation and protein analysis. Contractility responses to field and agonist-mediated stimulation (KCl and bethanecol) were analyzed. The expression patterns of alpha-smooth muscle actin, myosin, desmin, vimentin, and collagen III and I were analyzed by immunohistochemistry and Western blotting. Spatial and temporal distribution of nerve fibers within the detrusor muscle was monitored by neurotubulin-beta-III throughout gestation. Neither OIL, MMC, nor RA detrusor responded to field stimulation. MMC bladder strips showed a significant decrease in contractility after KCl and bethanechol stimulation compared with OIL and RA bladders. Bladder detrusor morphology and expression patterns of smooth muscle markers were similar between groups. Detrusor muscles in OIL and RA fetuses were densely innervated, possessing abundant intramural ganglia and nerve trunks that branch to supply smooth muscle bundles. In MMC bladders, neurotubulin-beta-III-positive nerve fibers were markedly decreased with advancing gestational age and were almost completely absent at term (E22). We conclude that the biomechanical properties of fetal rat MMC bladders are analogous to that seen in humans with MMC-associated NBD. Decreased nerve density indicates loss of peripheral neural innervation throughout gestation. The early observation of decreased innervation and decreased contractility in the absence of morphologic abnormalities in muscle structure or extracellular matrix supports a pathophysiological hypothesis that denervation is the primary insult preceding the observed alterations in bladder muscle structure and function.

    Title Smooth Muscle Trans-membrane Sarcoglycan Complex in Partial Bladder Outlet Obstruction.
    Date December 2006
    Journal Histochemistry and Cell Biology
    Excerpt

    The urinary bladder experiences both distension and contraction as a part of the normal filling and emptying cycle. To empty properly, tension generated intracellularly in a smooth muscle cell must be smoothly and efficiently transferred across its sarcolemma to the basement membrane, which mediates its binding to both the extracellular matrix and to other cells. As a consequence of urethral obstruction, the bladder cannot generate appropriate force to contract the organ, thereby leading to inefficient emptying and associated sequelae. In this study, an animal model of urethral obstruction was utilized to study the membrane-associated structures that transfer tension across the sarcolemma of bladder smooth muscle cells. Immunohistochemical localization of key components of the smooth muscle tension transfer apparatus (TTA) was performed utilizing specific antibodies against:(1) the alpha-chains of type IV collagen, a basement membrane component, and (2) beta-sarcoglycan, an integral membrane protein that is a participant in the physical linkage between the cytoskeleton and the basement membrane. We demonstrate, in obstructed animals, that there is a pronounced disruption of the TTA with a physical displacement of these two components that can be demonstrated at the level of the light microscope using scanning confocal microscopy. Electron microscopy further demonstrates significant increases in the size of the junctional plaques between smooth muscle cells.

    Title Partial Bladder Outlet Obstruction Selectively Abolishes Protein Kinase C Induced Contraction of Rabbit Detrusor Smooth Muscle.
    Date December 2006
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Despite the acute onset, partial bladder outlet obstruction in the rabbit induces detrusor remodeling similar to that in men with benign prostatic hyperplasia in terms of its impact on structural and functional alterations in smooth muscle. We determined if partial bladder outlet obstruction induced remodeling alters the protein kinase C signaling pathway that leads to contraction. MATERIALS AND METHODS: Smooth muscle from control animals and those subjected to 2 weeks of partial bladder outlet obstruction were mounted for isometric force recording, measurement of myosin light chain phosphorylation and levels of adducin phosphorylation. Bladder muscle strips were stimulated by phorbol dibutyrate or carbachol in the presence and absence of bisindolylmaleimide-1. RESULTS: Smooth muscle strips from animals subjected to partial bladder outlet obstruction showed little to no increase in stress in response to phorbol dibutyrate and no increase in myosin light chain phosphorylation levels. Muscle strips from control animals produced a robust contraction with concomitant increases in myosin light chain phosphorylation. Inhibition of protein kinase C by bisindolylmaleimide-1 significantly depressed carbachol induced contractions of muscle strips from control animals but it had no effect on carbachol induced contractions of muscle strips from outlet obstructed animals. Phorbol dibutyrate increased phospho-adducin levels in muscle strips from the 2 animal sources, suggesting that protein kinase C could be activated. CONCLUSIONS: We propose that partial bladder outlet obstruction does not alter protein kinase C activation, but rather abolishes or uncouples the pathway(s) downstream of protein kinase C, leading to contraction. Loss of this pathway may contribute to the loss of normal voiding behavior and the resultant decompensated state.

    Title Activation of the Calcineurin Pathway is Associated with Detrusor Decompensation: a Potential Therapeutic Target.
    Date September 2006
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We hypothesized that the calcineurin pathway mediated some of the complex remodeling process that allows a bladder subjected to partial outlet obstruction to adapt to its new workload. Atrial natriuretic factor mRNA expression served as a marker of calcineurin activation. MATERIALS AND METHODS: A total of 16 New Zealand White rabbits underwent surgical creation of partial outlet obstruction, followed by randomization to receive cyclosporin A (20 mg/kg intramuscularly twice daily) or no additional treatment for 14 days. Three animals underwent 2 weeks of partial bladder outlet obstruction followed by bladder biopsy and the reversal of obstruction. RESULTS: Atrial natriuretic factor expression was seen only in bladders with severe hypertrophy and it disappeared with the reversal of outlet obstruction. Cyclosporin A treatment resulted in a decrease in atrial natriuretic factor mRNA expression (p <0.05) and a marked shift in myosin heavy chain A-to-B ratios toward normal (p <0.01) and an increase in smooth muscle cross sectional area (p <0.05). Bladder mass decreased 40% but did not attain statistical significance (p = 0.08). CONCLUSIONS: The calcineurin pathway has a significant role in bladder wall hypertrophy following partial outlet obstruction. Bladder hypertrophy could not be fully prevented by cyclosporin A, suggesting that multiple signaling pathways are involved in this pathophysiology. The expression of myosin heavy chain AB isoforms is regulated in part by the calcineurin pathway.

    Title The Value of Imaging at the Time of Symptomatic Presentation.
    Date June 2006
    Journal Pediatric Emergency Care
    Title Altered Expression of Thin Filament-associated Proteins in Hypertrophied Urinary Bladder Smooth Muscle.
    Date March 2006
    Journal Neurourology and Urodynamics
    Excerpt

    AIMS: Obstruction of the urinary bladder outlet induces detrusor smooth muscle (DSM) hypertrophy. The goal of this study was to determine whether the composition of thin filament-associated proteins, known to play important roles in cytoskeletal structure and/or the regulation of contraction, is altered in DSM during hypertrophy. METHODS: DSM hypertrophy was induced in male rabbits by partial ligation of the urethra. Sham-operated rabbits served as a control. Reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time PCR revealed a significant increase in the expression of mRNAs for basic (h1) calponin (CaP), and alpha-isoform of tropomyosin (Tm) in hypertrophied DSM compared to controls. Western blotting and two-dimensional (2-D) gel electrophoresis showed enhanced expression of these proteins and also a significant increase in the expression of beta-non muscle and gamma-smooth muscle actin in the DSM from obstructed bladders, while alpha-actin remained constant. RESULTS: Enhanced expression of these proteins in the DSM from obstructed bladders was confirmed by immunofluorescence microscopy. Double immunostaining with Cap/Tm and alpha/beta-actin-specific antibodies showed co-localization of these proteins in myocytes. Colocalization of smooth muscle specific myosin and CaP to cytoplasmic filaments in cells dissociated from the hypertrophied DSM indicated that these cells are differentiated smooth muscle cells. CONCLUSIONS: The change in the isoforms of actin, Cap, and Tm may be part of the molecular mechanism for bladder compensation in increased urethral resistance.

    Title Partial Bladder Outlet Obstruction Induces Urethral Smooth Muscle Hypertrophy and Decreased Force Generation.
    Date February 2006
    Journal The Journal of Urology
    Excerpt

    PURPOSE: PBOO leads to increased urinary frequency, decreased void volume, hypertrophy of the detrusor SM, and alterations in contractile and regulatory proteins. This study was done to determine whether PBOO induced increases in urinary frequency and detrusor SM hypertrophy are associated with an alteration in the contractility and expression of myosin isoforms in urethral SM. MATERIALS AND METHODS: PBOO was surgically induced in male New Zealand White rabbits, and sham operated rabbits served as controls. After surgery, rabbits were kept 12 days, and prior to sacrifice, urine output and voiding frequency were monitored by keeping the animals in metabolic cages for 24 hours. Animals with increased urinary frequency (mean +/- SEM 43 +/- 12 voids per 24 hours) and sham operated rabbits (6 +/- 3 voids per 24 hours) were used for this study. Morphology of the urethra was studied using light and immunofluorescence microscopy. The expression of myosin isoforms was analyzed at the mRNA and protein levels by RT-PCR and Western blotting. RESULTS: The urethral wall and SM of PBOO rabbits showed hypertrophy. The force produced by the longitudinal muscle strips of PBOO animals in response to phenylephrine, KCl, or electrical field stimulation was decreased 50%, 37% and 40%, respectively. Immunofluorescence microscopy revealed a decrease in nerve density. RT-PCR and Western blotting showed a decrease in the expression of myosin isoform SM-B with a concomitant increase in SM-A at the mRNA and protein levels. CONCLUSIONS: Our data show hypertrophy of the urethral wall and SM, and alterations in contraction, innervation, and myosin isoforms in PBOO induced detrusor hypertrophy.

    Title Testicular Microlithiasis and Antisperm Antibodies Following Testicular Biopsy in Boys with Cryptorchidism.
    Date November 2005
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Testicular biopsy (TBx) performed during orchiopexy in boys with cryptorchidism can help to predict future semen analyses and possibly identify patients at risk for testicular cancer. It has been theorized that TBx can be detrimental to the long-term health of the testis. We examined testicular microlithiasis (TM) and antisperm antibody (ASA) production in cryptorchid TBx. MATERIALS AND METHODS: A total of 112 males underwent fertility evaluation. These patients had previously undergone orchiopexy and bilateral TBx (mean age 8.6 years) for unilateral or bilateral undescended testis. At a mean age of 19.6 years all patients underwent physical examination and scrotal ultrasound for evaluation of testis size, echotexture and abnormalities. Of 112 patients 57 also underwent direct Immunobead(R) assay with positive controls. Moving sperm free and/or bound to IgG bead complex were counted in the preparation. RESULTS: A total of 29 patients had bilateral and 83 had unilateral undescended testis. Of the 112 patients 26 were black and 86 were white. Four black patients (15.4%) and 4 white patients (4.7%) had testicular microlithiasis. Three patients had bilateral and 5 had unilateral diffuse TM. No tunica albuginea scars or testis masses were noted. In the 57 patients who underwent direct Immunobead assay no semen sample demonstrated evidence of forming bead-sperm complex, ie none had direct ASA. CONCLUSIONS: No patient exhibited evidence of direct ASA. Prepubertal open TBx does not increase the rate of TM. We found no evidence of additive testicular damage associated with TBx at the time of orchiopexy.

    Title Increased Corpus Cavernosum Smooth Muscle Tone Associated with Partial Bladder Outlet Obstruction is Mediated Via Rho-kinase.
    Date November 2005
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Numerous studies have now demonstrated that lower urinary tract symptoms (LUTS) are associated with erectile dysfunction (ED) in men independent of age or general health. Because one-third of men over the age of 50 will develop LUTS and a recent study showed ED in 62% of patients presenting for LUTS, the importance of determining the mechanistic link between these two pathologies is clear. Using a rabbit model of partial bladder outlet obstruction (PBOO), a primary cause of LUTS, we have identified an increased basal corpus cavernosum smooth muscle (CCSM) tone associated with an elevated level of smooth muscle myosin (SMM) phosphorylation in PBOO compared with sham-operated control rabbits (sham). Results from in vitro kinase and phosphatase assays using purified smooth muscle myosin showed increased kinase and decreased phosphatase activities in cellular extracts from corpora cavernosa isolated from PBOO compared with sham rabbits. Increased Rho-kinase expression in the CCSM of PBOO rabbits was suggested by the observations that Rho-kinase inhibitors attenuated the increased kinase activity and were less effective in relaxing CCSM strips from PBOO vs. sham rabbits. This hypothesis was then confirmed by RT-PCR and Western blotting, which demonstrated increased expression of both isoforms of Rho-kinase (ROKalpha and ROKbeta). Increased SMM basal phosphorylation (necessary for SM contraction) in the CCSM of PBOO rabbits, mediated via an increase in Rho-kinase expression/activity, would be expected to make the CCSM more difficult to relax (necessary for erection), which suggests that the RhoA/Rho-kinase pathway as being involved in the mechanism for LUTS-associated ED.

    Title Overnight Catheter Drainage in Children with Poorly Compliant Bladders Improves Post-obstructive Diuresis and Urinary Incontinence.
    Date October 2005
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Overnight catheter drainage (OCD) has been suggested as a treatment for boys with valve bladder syndrome as well as those with polyuric renal failure. We report our experience using overnight catheter drainage in children with poorly compliant bladders. MATERIALS AND METHODS: Between 1999 and 2004 OCD was initiated in 6 boys and 5 girls (median age 7.5 years) with poorly compliant bladders in whom aggressive daytime intermittent catheterization and anticholinergic use had failed. Etiologies of bladder dysfunction included posterior urethral valves in 1 case, The Hinman-Allen syndrome in 4, myelomeningocele in 2, neuroblastoma in 1, prune-belly syndrome in 1, transverse myelitis in 1 and sacral agenesis in 1. The amount of post-obstructive diuresis was calculated during urodynamics as the volume drained minus volume instilled divided by weight per hour. Other parameters evaluated included serum creatinine, degree of upper tract dilatation, and episodes of urinary tract infection (UTI) and incontinence. RESULTS: Median duration of OCD and followup was 28 months, respectively. One patient did not tolerate overnight drainage. Of 9 patients who were incontinent before OCD daytime urinary incontinence resolved in 6 and improved in 3. Recurrent febrile UTIs in 3 children were eliminated. Despite no change in serum creatinine with overnight drainage, 7 of 8 patients (88%) with upper tract dilatation improved on followup ultrasound. CONCLUSIONS: In select children with poorly compliant bladders OCD reduces diuresis, reduces the frequency of UTIs, improves upper tract dilatation and improves continence. Overnight drainage in conjunction with daytime clean intermittent catheterization may prove to be an alternative to bladder augmentation in select children with poorly compliant bladders and early stages of renal compromise.

    Title Prenatally Detected Primary Megaureter: a Role for Extended Followup.
    Date April 2005
    Journal The Journal of Urology
    Excerpt

    PURPOSE: A high rate of spontaneous resolution of or decrease in urinary tract dilatation is expected for most cases of primary megaureter (PM). We analyzed our results with extended long-term nonsurgical treatment in a group of children diagnosed with prenatally detected PM. We also sought to determine the long-term safety of this approach and the clinical significance of residual hydroureteronephrosis (HUN) when complete resolution does not occur. MATERIALS AND METHODS: We reviewed our experience with 40 infants with prenatally detected hydronephrosis diagnosed as PM who were initially treated nonoperatively between 1986 and 1999. Patients were followed with ultrasonography, nuclear renography and, in some instances, excretory urogram until stable improvement or complete resolution of HUN was noted. Records for patients who specifically returned for long-term followup history and radiological imaging were also reviewed. RESULTS: Of 40 patients with 57 megaureters (17 with bilateral PMs) who were followed 4 infants (10%) with severe HUN were diagnosed with diminished renal function by nuclear renography and underwent surgical repair. A total of 27 infants (67.5%, 40 megaureters) with PM who were followed without surgical intervention returned for followup examination and imaging for a minimum of 24 months after initial diagnosis, for a mean of 6.8 years (range 24 to 210 months). Ultrasonography in these patients revealed complete resolution (Society for Fetal Urology grade 1 or less hydronephrosis) in 21 megaureters (52.5%) at a mean of 2.9 years and improved or stable HUN in 19 megaureters (47.5%). Antibiotic prophylaxis was administered to 12 patients beyond the first month of life and discontinued at a mean age of 19.9 months. A subgroup of 10 patients (16 megaureters) from this cohort returned for extended followup imaging at a mean of 13.4 years (range 84 to 210 months) following initial diagnosis. Four patients with documented resolution of HUN had no recurrence during long-term followup. One male with bilateral PMs diagnosed at birth that had been stable but were not resolved at 8-year followup suffered significant worsening in the degree of HUN, diminished renal function on 1 side and a renal stone on the contralateral renal unit at 14-year followup, despite remaining asymptomatic. CONCLUSIONS: Long-term followup of children with prenatally diagnosed PM with mild to moderate hydronephrosis confirms a high incidence of resolution and improvement. As we have documented 1 case of worsening HUN at 14-year followup, we believe that ultrasonography should be periodically continued until the child reaches adulthood, at least in instances where complete resolution of HUN is not documented.

    Title Regional Alterations in the Expression of Smooth Muscle Myosin Isoforms in Response to Partial Bladder Outlet Obstruction.
    Date January 2005
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Smooth muscle (SM) myosin (SMM) isoform composition is altered in response to partial bladder outlet obstruction (PBOO). A recent study showed that during PBOO the upper dome region of the bladder is subjected to greater expansion pressure than the base and regional differences in contractility exist in the detrusor of PBOO rabbits. We hypothesized that alteration in SMM isoform composition in response to PBOO may show regional heterogeneity. MATERIALS AND METHODS: Detrusor samples were obtained from 9 defined regions of the bladders from dysfunctional PBOO rabbits (greater than 30 voids per 24 hours) and sham operated adult New Zealand White rabbits. Reverse transcriptase-polymerase chain reaction, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting were used to determine the relative levels of SMM isoform expression at the mRNA and protein levels. Contractile responses to bethanechol and KCl were also determined. RESULTS: Myosin isoform expression was uniform throughout the detrusor from sham operated subjects with all regions expressing SM-B almost completely. However, in response to PBOO the dome region showed approximately 70% SM-B and 30% SM-A isoforms, whereas the base region expressed only 35% SM-B and, thus, 65% SM-A. This change also correlated with an approximately 2-fold higher protein level expression of SM-B in the dome region of PBOO rabbit bladders. Expression of the SMemb SMM isoform was significantly increased in PBOO rabbits at the mRNA and protein levels but only in the dome region. Regional differences in SMM isoform expression in the PBOO rabbit bladders correlated with altered contractility. CONCLUSIONS: Alteration in SMM isoform composition in response to PBOO shows regional heterogeneity and may be involved in the mechanism responsible for regional localized differences in detrusor contractility in PBOO rabbits.

    Title Giant Bladder Diverticula Causing Bladder Outlet Obstruction in Children.
    Date January 2005
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Congenital giant diverticulum of the bladder is a consequence of deficiency in the detrusor musculature and has been reported in male infants as a rare cause of bladder outlet obstruction. MATERIALS AND METHODS: A 10-year retrospective review revealed 4 patients (3 boys and 1 girl) with bladder outlet obstruction due to a giant bladder diverticulum. Prenatal and postnatal clinical and imaging records were reviewed. RESULTS: Prenatal sonography was unremarkable in all patients. Three males (ages 4 months, 10 months and 3 years) had no medical history of voiding dysfunction, and 1 female (11 years) had the Ehlers-Danlos syndrome. While the girl presented with urinary tract infection, all patients presented with progressively decreasing urinary stream and urinary retention. Each patient underwent voiding cystourethrography (VCUG) and ultrasound. In each patient VCUG showed a giant (greater than 7 cm) bladder diverticulum that descended below the bladder neck and compressed the urethra during voiding. Vesicoureteral reflux was seen in 2 patients. Ultrasonography demonstrated moderate unilateral hydronephrosis in 2 patients. Bladder diverticulectomy was successfully performed in all patients, with ureteral reimplantation in 3. CONCLUSIONS: A giant congenital bladder diverticulum, when noted on VCUG to descend below the bladder neck, may lead to bladder outlet obstruction. To our knowledge we report the first case of a female presenting with bladder outlet obstruction due to a giant bladder diverticulum. Children with connective tissue disorders may be predisposed to this disorder, which must be excluded, regardless of gender, in all patients presenting with voiding abnormalities. Surgical diverticulectomy, often with ureteral reimplantation, is the preferred treatment, with excellent long-term results.

    Title A Male Murine Model of Partial Bladder Outlet Obstruction Reveals Changes in Detrusor Morphology, Contractility and Myosin Isoform Expression.
    Date November 2004
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Mice with gene deletion or targeted over expression are important for understanding the remodeling that follows partial bladder outlet obstruction (PBOO). This condition predominates in males. We produced PBOO in male mice and now report the physiological, histological and molecular consequences. MATERIALS AND METHODS: Male C57bl/6 mice were surgically obstructed or subjected to sham surgery and unoperated mice served as controls. Four weeks later the bladders were excised and their function was assessed with in vitro whole bladder cystometry. The optimum volume for pressure generation was determined and isometric pressures were measured for field stimulation and depolarization with KCl. Bladder hypertrophy was classified as severe-bladder mass greater than 50 mg or mild-bladder mass less than 50 mg. The percent muscle fraction was determined by histological analyses. The expression of C-terminal (SM1 and SM2) and N-terminal (SM-B and SM-A) isoforms of myosin heavy chain was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: Severely hypertrophied bladders had larger optimum volume (p >0.001) and generated less pressure in response to field stimulation (p >0.001) and KCl (p >0.01) with a slower rate of pressure generation than controls or sham operated mice. Increased SM1-to-SM2 and SM-A-to-SM-B ratios were noted in severely obstructed bladders relative to controls or sham operated mice (p <0.05). The muscle fraction decreased slightly in the severely hypertrophied group (p not significant). CONCLUSIONS: Our male mouse model of PBOO demonstrates an increase in bladder mass, larger capacity and significantly decreased pressure generation in the in vitro whole bladder model. Obstruction induced increases in the expression of C-terminal (SM1) and N-terminal (SM-A) myosin heavy chain isoforms.

    Title Partial Bladder Outlet Obstruction Abolishes the Receptor- and G Protein-dependent Increase in Calcium Sensitivity in Rabbit Bladder Smooth Muscle.
    Date October 2004
    Journal American Journal of Physiology. Renal Physiology
    Excerpt

    Partial bladder outlet obstruction (PBOO) alters the function of the whole bladder and produces specific alterations in the contractility of the bladder smooth muscle cell. The goal of this study was to test the hypothesis that PBOO affects smooth muscle contraction at the level of the receptor- and G protein-dependent increase in myofilament Ca2+ sensitivity. To address this question, we used alpha-toxin-permeabilized strips of bladder smooth muscle from control animals and animals subjected to 2 wk of PBOO. Increasing free [Ca2+] increased force in permeabilized strips from control animals; the addition of 10 microM carbachol and 10 microM GTP increased both the Ca2+ sensitivity of the contractions and the maximal levels of force attained. In contrast, although increases in [Ca2+] increased force in permeabilized strips from PBOO animals, the addition of carbachol and GTP had no additional effects. Myosin light chain phosphorylation levels increased with [Ca2+], and although they tended to be higher in strips from PBOO animals, they did not reach statistical significance. Assessment of G protein activity from both animal models suggests this is not a site responsible for the loss of carbachol and GTP enhancement of myofilament Ca2+ sensitivity. The addition of phorbol dibutyrate increased the Ca2+ sensitivity of force development in strips from both animal models, suggesting that an alteration in PKC signaling is not involved. Our results are consistent with the hypothesis that PBOO decreases receptor-mediated myofilament calcium sensitization and that the site of action is downstream from either the G proteins or PKC.

    Title The Physical Characteristics of Young Males with Varicocele.
    Date October 2004
    Journal Bju International
    Excerpt

    OBJECTIVE: To determine if there is an association with habitus in young males with varicocele, as adolescent boys with varicoceles appear to be mostly taller and leaner than age-matched controls. PATIENTS AND METHODS: Retrospectively reviewing our records we obtained the height and weight of 43 consecutive males (mean age 14.3 years, range 11-19) under long-term follow-up for varicocele. The body mass index (BMI), heights and weights were compared with values from the respective growth charts for boys aged 2-20 years (Center for Disease Control and Prevention), and the statistical significance of differences determined using the chi-square test. RESULTS: The height and weight distributions of patients with varicocele indicated a significant deviation from normal in the 25-95th percentiles for stature and in the 25-75th for weight (P < 0.05). Deviations in BMI were insignificantly different from normal at each percentile. CONCLUSION: These results indicate that patients with varicocele are significantly taller and heavier than age-matched controls. Future studies to address the key areas identified in this study will help to further assess the distribution of the incidence of varicocele in closely defined subsets of adolescent growth and development, which may provide some insight into the cause of varicoceles.

    Title Renal and Adrenal Tumors in Children.
    Date October 2004
    Journal The Urologic Clinics of North America
    Excerpt

    Survival rates for children with kidney tumors approach 90% for even the most advanced stages of disease, but the surgical management of large lesions remains challenging.With the development of additional chemotherapeutic regimens and the use of radiation therapy, survival rates have improved dramatically. The National Wilms' Tumor Study has conducted four long-term studies addressing how adjunctive therapy may be tailored optimally to maximize survival and minimize the exposure to chemotherapy and radiation therapy.

    Title Murine in Vitro Whole Bladder Model: a Method for Assessing Phenotypic Responses to Pharmacologic Stimuli and Hypoxia.
    Date August 2004
    Journal Neurourology and Urodynamics
    Excerpt

    AIMS: Recent advances in genetic manipulation have allowed for over expression or deletion of selective genes in mice. This offers urologic investigators new means of understanding bladder function in the context of normal development or the response to outlet obstruction. It is important to correlate any genetic manipulations in mice with specific phenotypic properties such as voiding patterns, or muscle strip physiology. We describe a simple in vivo whole bladder preparation that may be used to study the phenotypic changes in bladder function. METHODS: Murine bladders were mounted on a 30 gauge needle and mounted in an organ chamber containing a physiologic buffer solution. Passive bladder properties were assessed with cystometry, and active contractile responses were measured in response to electrical field stimulation and agonists. The effects of hypoxia were also studied. RESULTS: Compliance in the murine bladder is dependent upon actin myosin interactions, and increased in the presence of calcium free buffer and EGTA. The sarcoplasmic reticulum plays a smaller role in the contraction of murine bladder than in other species. Murine bladder smooth muscle demonstrated a remarkable ability to withstand hypoxia. CONCLUSIONS: This simple model can be adapted to help study the murine bladder smooth muscle phenotype under highly controlled circumstances.

    Title The Fate of Urinary Bladder Smooth Muscle After Outlet Obstruction--a Role for the Sarcoplasmic Reticulum.
    Date June 2004
    Journal Advances in Experimental Medicine and Biology
    Title Murine in Vitro Whole Bladder Physiology.
    Date May 2004
    Journal Advances in Experimental Medicine and Biology
    Title Over Expression of Smooth Muscle Specific Caldesmon by Transfection and Intermittent Agonist Induced Contraction Alters Cellular Morphology and Restores Differentiated Smooth Muscle Phenotype.
    Date May 2004
    Journal The Journal of Urology
    Excerpt

    PURPOSE: The thin filament associated protein h-caldesmon (h-CaD) modulates actin myosin interaction and contraction. Bladder outlet obstruction and detrusor hypertrophy are associated with the over expression of the nonmuscle CaD isoform l-CaD. It implies a poorly differentiated state of bladder myocytes and cytoskeletal remodeling in detrusor hypertrophy. We determined if h-CaD expression can be increased in a unique bladder smooth muscle (BSM) cell line derived from obstructed rabbit bladder smooth muscle that over expresses l-CaD. We examined whether the genetic restoration of h-caldesmon is possible in bladder smooth muscle cells by transfection or by agonist mediated contraction and whether this manipulation would alter cellular morphology. MATERIALS AND METHODS: BSM cells were transfected with chicken h-CaD cDNA inserted into a mammalian vector. In another experiment BSM cells underwent intermittent bethanechol induced stimulation. h-CaD mRNA and protein were quantified with reverse transcriptase-polymerase chain reaction and Western blot analyses. Cell morphology was assessed using phase, video and confocal microscopy after double immunostaining with antibodies against alpha-actin and caldesmon. RESULTS: Reverse transcriptase-polymerase chain reaction using primers specific for the transfected vector and h-CaD cDNA confirmed stable transfection of cells and increased content of h-CaD mRNA. Following bethanechol induced intermittent contraction Western blotting revealed 80% relative over expression of h-CaD in treated transfected cell lines (p <0.05) and 74% (not significant) in treated nontransfected controls. Confocal immunofluorescence microscopy revealed CaD in the cytoplasmic filaments co-localized to alpha-actin in the main cell body and perinuclear region in transfected cells, in contrast to the diffuse, irregular distribution of these filaments in control cells. CONCLUSIONS: A unique bladder myocyte cell line was successfully and stably transfected with h-CaD cDNA. We show that agonist induced intermittent contraction preferentially increases h-CaD expression, the predominant CaD in nonobstructed bladder smooth muscle, and the restoration of h-CaD alters cell morphology and the organization of cytoplasmic filaments in cells derived from obstructed rabbit detrusor musculature.

    Title Smooth Muscle Hypertrophy Following Partial Bladder Outlet Obstruction is Associated with Overexpression of Non-muscle Caldesmon.
    Date March 2004
    Journal The American Journal of Pathology
    Excerpt

    Partial bladder outlet obstruction (PBOO) induces remodeling of urinary bladder smooth muscle (detrusor). We demonstrate an increase in bladder wall mass, muscle bundle size, and a threefold increase in the cross-sectional area of detrusor myocytes following PBOO in male New Zealand White rabbits compared to that of controls. Some bladders with detrusor hypertrophy function close to normal (compensated), whereas others were dysfunctional (decompensated), showing high intravesical pressure, large residual urine volume, and voiding difficulty. We analyzed the expression of smooth muscle-specific caldesmon (h-CaD) and non-muscle (l-CaD) by Western blotting, RT-PCR, and real-time PCR. The expression of l-CaD is increased significantly at the mRNA and protein levels in the decompensated bladders compared to that of normal and compensated bladders. The CaD was also co-localized with myosin containing cytoplasmic fibrils in cells dissociated from obstructed bladders and cultured overnight. Our data show that the inability of decompensated bladders to empty, despite detrusor hypertrophy, is associated with an overexpression of l-CaD. The level of l-CaD overexpression might be a useful marker to estimate the degree of detrusor remodeling and contractile dysfunction in PBOO.

    Title Decrease in Maximal Force Generation in the Neonatal Mouse Bladder Corresponds to Shift in Myosin Heavy Chain Isoform Composition.
    Date February 2004
    Journal The Journal of Urology
    Excerpt

    PURPOSE: A change in calcium handling has been proposed as the cause of decreased maximal force generation by neonatal bladders with growth. Recent studies suggest that increased myosin heavy chain isoform SM1 increases force generation. We studied force generation in neonatal mouse bladders to determine if decreases in SM1 corresponded with decreased force. MATERIALS AND METHODS: C57Bl/6 mice were studied from birth to 12 weeks of life (adulthood). The bladder strip contractile response to KCl and bethanechol was followed by the inhibition of rho-kinase activity by Y-27632. The mRNA levels for SM1/SM2 were determined using reverse transcriptase-polymerase chain reaction and protein levels were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Muscle fraction per cross-sectional area was determined by trichrome staining. RESULTS: Newborn bladders generated significantly more tension in response to KCl (43.3 vs 17.4 mN/mm2, p = 0.02) and bethanechol (40.6 vs 11.9 mN/mm2, p = 0.05) than adult bladders. Inhibition of rho-kinase resulted in similar decreases in tension in all bladders. SM1 mRNA decreased slightly from 60% at birth to 50% at 12 weeks. SM1 protein decreased from 72.5% at birth to 50% by 3 weeks and it remained stable at 12 weeks. Total myosin per gm protein remained stable. Muscle fraction decreased from 63.8% at birth to 58.6% at 12 weeks (p = 0.4). CONCLUSIONS: We noted a decrease in SM1 that corresponded to a decrease in bladder force generation. The concept that SM1 contributes to the optimal assembly of myosin filaments suggests that changes in myosin isoforms may have a role in the decrease in voiding pressures seen in normal children.

    Title Persistent Mullerian Duct Syndrome Associated with 47,xxy Genotype.
    Date February 2004
    Journal The Journal of Urology
    Title Experience with Testis Sparing Surgery for Testicular Teratoma.
    Date January 2004
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Testicular teratoma is a rare neoplasm affecting the pediatric population and has classically been reported to be the second most common testis tumor in children behind yolk sac tumors. Testicular teratomas are benign and partial orchiectomy may be considered. We describe our single institution experience with testicular teratoma and definitive treatment with testis preserving surgery. MATERIALS AND METHODS: We reviewed the pathology records at our institution for all testicular and paratesticular tumors diagnosed between 1976 and November 2002 in males younger than 18 years. We specifically examined the prepubertal incidence of teratoma, including epidermoid cysts, and our experience with testis preserving surgery. Preoperative and postoperative ultrasonography images were used to calculate the atrophy index following surgery. Patients were contacted for long-term followup. RESULTS: Of 77 primary testicular and paratesticular tumors 38 were diagnosed in prepubertal boys (age younger than 13 years) including 11 mature teratomas and 5 epidermoid cysts. Mean patient age at treatment was 34.4 months (range 4 months to 10 years). All boys presented with a painless scrotal mass, cystic foci within an intratesticular mass on ultrasound and a normal alpha-fetoprotein level. Of the 16 boys with benign teratomas 13 (81%) were treated with a testis sparing procedure. At a mean 7-year followup no patient has presented with recurrent tumor in the ipsilateral or contralateral testicle. Postoperative physical examination and scrotal ultrasound were obtained in 9 patients at a median followup of 10.2 months, and there was no evidence of testicular atrophy or persistent discomfort. CONCLUSIONS: Unlike previously published series based on tumor registries, benign teratoma was the most common pediatric testicular tumor treated at our institution. Our single institution experience with testis preservation and long-term followup confirms the role and safety of this technique. Testis sparing surgery remains our technique of choice for testicular teratoma.

    Title Obstruction-induced Changes in Urinary Bladder Smooth Muscle Contractility: a Role for Rho Kinase.
    Date December 2003
    Journal American Journal of Physiology. Renal Physiology
    Excerpt

    Detrusor smooth muscle (DSM) undergoes hypertrophy after partial bladder outlet obstruction (PBOO) in male rabbits, as it does in men with PBOO induced by benign prostatic hyperplasia. Despite detrusor hypertrophy, some bladders are severely dysfunctional (decompensated). In this study, the rabbit model for PBOO was used to determine the biochemical regulation of the contractile apparatus and force maintenance by the detrusor from decompensated bladders (DB). Bladders from sham-operated rabbits served as a control. On stimulation with 125 mM KCl, the DSM from sham-operated (SB) rabbits showed phasic contractions, whereas the detrusor from DB was tonic, exhibiting slow development of force, a longer duration of force maintenance, and slow relaxation. The Rho kinase (ROK) inhibitor Y-27632 enhanced the relaxation of precontracted DSM strips from DB. The enhancement of relaxation of the KCl-induced contraction of DB by Y-27632 was associated with dephosphorylation of myosin light chain (MLC20). The DSM extract from DB showed low phosphatase activity compared with that from SB. The DB also showed more Ca2+-independent MLC20 phosphorylation, which was partially inhibited by Y-27632. RT-PCR and Western blotting revealed similar expression levels of MLC kinase and ROK-alpha in SB and DB, but ROK-beta was overexpressed in DB. These results suggest that the ROK-mediated pathway is partly responsible for the high degree of force maintenance and slow relaxation in the detrusor from DB.

    Title Partial Bladder Outlet Obstruction Alters Ca2+ Sensitivity of Force, but Not of Mlc Phosphorylation, in Bladder Smooth Muscle.
    Date October 2003
    Journal American Journal of Physiology. Renal Physiology
    Excerpt

    Partial bladder outlet obstruction in the rabbit produces changes in bladder function similar to those seen clinically in patients with obstructive uropathies. Whole organ function is significantly altered, as are the smooth muscle cells inside the bladder wall. This study was designed to determine whether outlet obstruction alters smooth muscle function at the level of contractile filaments. Rabbit bladders were partially obstructed for 2 wk. Triton X-100 was used to provide a detergent-skinned bladder smooth muscle preparation that would allow control of the intracellular environment while the ability to shorten and develop force is maintained. Ca2+-force and Ca2+-myosin light chain (MLC) phosphorylation relations and maximal velocity of shortening were determined. The Ca2+ sensitivity of force was significantly lower in tissues from animals subjected to outlet obstruction compared with tissues from control animals. In contrast, no difference was noted in the Ca2+ sensitivity of MLC phosphorylation. Maximal levels of stress and MLC phosphorylation were similar in both animal groups. Maximal velocity of shortening was significantly slower in tissues from outlet-obstructed animals at all Ca2+ concentrations compared with tissues from control animals. Ultrastructurally, detergent skinning had little effect on structural integrity. Moreover, tissues from obstructed animals showed an increase in the number of sarcolemmal attachment plaque structures. We suggest that partial bladder outlet obstruction produces deleterious (e.g., decrease in Ca2+ sensitivity of force) and compensatory (e.g., increase in membrane attachment plaques) changes in bladder smooth muscle cells.

    Title The Chop Experience with Cloacal Exstrophy and Gender Reassignment.
    Date August 2003
    Journal Advances in Experimental Medicine and Biology
    Title Testis Histopathology in Boys with Cryptorchidism Correlates with Future Fertility Potential.
    Date February 2003
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We studied the ability of testis biopsy to predict eventual fertility potential. MATERIALS AND METHODS: A total of 25 patients with unilateral undescended testis and 11 with bilateral undescended testes who previously underwent orchiopexy at a median age of 9 years were followed until after age 18 years. Semen analysis, testicular volume, follicle-stimulating hormone, luteinizing hormone, testosterone and inhibin B were compared to previously obtained biopsies of each testis. Biopsies were graded as mild, moderate or severe histology based on published data for normal and undescended testis histology. RESULTS: Patients with unilateral undescended testis and moderate histology were more likely to have a sperm density of greater than 20 million per cc than those with severe histology (p = 0.006), although no difference in hormonal parameters was noted. Patients with bilateral undescended testes and moderate histology were more likely to have normal follicle-stimulating hormone and inhibin B than those with severe histology (p = 0.05 and 0.002, respectively), although no difference in semen analysis was observed. Overall 7 of the 9 patients with bilateral undescended testes had less than 20 million sperm per cc. CONCLUSIONS: Testis biopsy provides useful prognostic information about semen analysis in patients with unilateral undescended testis. In the 9 patients with bilateral undescended testes testis biopsy divided them into normal and abnormal groups in terms of hormonal parameters. Testis biopsy was not able to provide additional prognostic information on semen analysis in patients with bilateral undescended testes since they were uniformly poor.

    Title The Ascending Testis and the Testis Undescended Since Birth Share the Same Histopathology.
    Date December 2002
    Journal The Journal of Urology
    Excerpt

    PURPOSE: The etiology of the ascending testis is controversial. We propose that ascending testis, defined as a testis previously thought to be descended and later noted to be out of the scrotum, is due to mild hypogonadotropic hypogonadism affecting both testes. The diagnosis of these low types of true undescended testes is difficult to make clinically in children since they are frequently confused with retractile testes. In this study we compared testicular biopsies in a group of boys with ascending testes with those in boys who had an undescended testis since birth (primary undescended testis). MATERIALS AND METHODS: Between 1985 and 1995, 91 patients with ascending testes underwent orchiopexy and bilateral testis biopsy. The total germ cell count, processus vaginalis status, age at surgery and whether followup was done by a pediatrician or pediatric urologist were compared in patients with ascending and unilateral primary undescended testes. RESULTS: The total germ cell count was similar in the undescended and the contralateral descended testis in patients with ascending and primary undescended testes. The processus vaginalis was more likely to be closed in ascending testes (57% versus 36%, p = 0.0001). Age at surgery and the total germ cell count were similar in patients followed by pediatricians and pediatric urologists. CONCLUSIONS: The ascending testis has the same germ cell count as the primary undescended testis. Yearly followup by the primary care physician is recommended for patients with retractile testes.

    Title Generation of a Cell Line with Smooth Muscle Phenotype from Hypertrophied Urinary Bladder.
    Date July 2002
    Journal American Journal of Physiology. Cell Physiology
    Excerpt

    We have established a cell line from hypertrophied rabbit urinary bladder smooth muscle (SM) that stably expresses SM myosin (SMM). These cells, termed BSM, are spindle shaped and form swirls, similar to the "hills and valleys" described for cultured aortic SM cells. Western blotting revealed that BSM expresses the amino-terminal SMM heavy chain isoform SM-B, the carboxy-terminal SM1 and SM2 isoforms, and SM alpha-actin. In addition, they express cGMP-dependent protein kinase G, made by contractile SM cells in vitro but not by noncontractile cells synthesizing extracellular matrix. Immunofluorescence studies indicate a homogeneous population of cells expressing alpha-actin and SMM, including the SM-B isoform, and karyotyping demonstrates a stable 4N chromosomal pattern. These cells also express calcium-dependent myosin light chain kinase and phosphatase activity and contract in response to the muscarinic agonist bethanechol. To our knowledge, BSM is the first visceral SM cell line that expresses the SM-B isoform and might serve as a useful model to study the transcriptional regulation of tissue-specific SMM isoforms in differentiation and pathological SM.

    Title Enhanced Force Generation by Corpus Cavernosum Smooth Muscle in Rabbits with Partial Bladder Outlet Obstruction.
    Date June 2002
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Growing clinical evidence suggests that benign prostatic hyperplasia induced partial bladder outlet obstruction is associated with an increased incidence of erectile dysfunction. We determined whether corpus cavernosum smooth muscle from rabbits with partial bladder outlet obstruction show any molecular or functional differences versus controls. MATERIALS AND METHODS: Force generation and relaxation of corpus cavernosum smooth muscle 2 weeks after partial bladder outlet obstruction by 125 mM. KCl, phenylephrine and field stimulation were determined. Expression of total smooth muscle myosin and alternatively spliced smooth muscle myosin isoforms were determined by reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative competitive RT-PCR, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis. Corpus cavernosum smooth muscle from sections of the penis were analyzed morphologically by immunofluorescence microscopy using antibodies to smooth muscle myosin and neurofilament protein. RESULTS: Corpus cavernosum smooth muscle from rabbits with partial bladder outlet obstruction generated 40% to 50% more force than that of sham operated rabbits in response to KCl or phenylephrine and was more difficult to relax. Although quantitative competitive RT-PCR and sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that corpus cavernosum smooth muscle from rabbits with partial bladder outlet obstruction expressed only slightly more total smooth muscle myosin at the messenger RNA and protein levels, expression of the high adenosine triphosphatase isoform SM-B increased 2-fold. Morphological examination of corpus cavernosum smooth muscle sections revealed decreased innervation and increased smooth muscle bundle size. CONCLUSIONS: We present the novel finding of molecular and functional changes in the corpus cavernosum smooth muscle associated with partial bladder outlet obstruction. Although the inclusion of sham operation ruled out direct injury during surgery, a change in corpus cavernosum smooth muscle innervation induced by nerve compression by the ligature is likely to induce trophic changes in the corpus cavernosum smooth muscle leading to over expression of the SM-B smooth muscle myosin isoform, increased contractility and impaired relaxation.

    Title The Use of Vesicostomy As Permanent Urinary Diversion in the Child with Myelomeningocele.
    Date December 2001
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Treatment of the child with myelomeningocele presents the urologist with many challenges. While vesicostomies are usually used for temporary bladder drainage until continent reconstruction is performed, we have a population of postpubertal patients with myelomeningocele in whom vesicostomies have been preserved. We review our experience with these older children. MATERIALS AND METHODS: A search of our database of 350 patients with myelodysplasia identified 23 with urinary diversion accomplished by permanent vesicostomy. Those who had undergone vesicostomy after age 11 years were designated as group 1. Those who received a vesicostomy early in life that was maintained post puberty were designated as group 2. Indications for vesicostomy, upper tract status before and after vesicostomy, recurrent infections and complications were noted. Upper tract status was determined by serial ultrasounds during routine followup. RESULTS: Group 1 was comprised of 5 patients with mean age at vesicostomy of 17 years and a mean followup interval of 5.2 years. Group 2 was comprised of 18 patients with mean age of vesicostomy at 2.6 years and mean followup interval of 13 years. Hydronephrosis resolved in all children from both groups. Vesicostomy revision was required in 1 patient secondary to prolapse. Other complications included mild prolapse that did not require revision, stenosis requiring revision 5 months after the initial procedure and an early bilateral ureterovesical obstruction that resolved. Of the patients 33% had recurrent upper tract calculi. CONCLUSIONS: While the goal of achieving urinary continence is well worth striving for in the child with myelomeningocele, it is not realistic for all patients. We believe that permanent cutaneous vesicostomy is an acceptable alternative that the reconstructive surgeon should consider. This reliable and simple technique ensures safe decompression of the upper urinary tracts, while avoiding the complications of urinary diversion using segments of bowel.

    Title Buccal Mucosal Grafts: Lessons Learned from an 8-year Experience.
    Date December 2001
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We evaluated our 8-year experience with buccal mucosal grafts in complex hypospadias and epispadias repair. MATERIALS AND METHODS: We reviewed the records of 29 patients in whom a total of 30 buccal mucosal grafts were placed as part of urethral reconstruction between 1991 and 1999. At surgery 16 tubes and 14 onlays were constructed and 24 of 30 repairs involved the meatus. All patients were followed at least 6 months postoperatively (median 5.3 years). Beginning in 1995 meatal design was enlarged to a racquet handle shape and patients were asked to perform meatal self-dilation for 6 months postoperatively. RESULTS: Complications developed in 17 of our 30 cases (57%) and reoperation was done in 10 (33%). All complications were evident by 11 months postoperatively except 1 that presented as recurrent stricture disease at 3 years. Complications developed in 5 and 12 of 15 patients who underwent surgery between 1995 and 1999, and before 1995, respectively (p = 0.027). No patient has had meatal stenosis since 1995. Complications included meatal stenosis in 5 cases, stricture in 7, glanuloplasty, meatal and complete graft breakdown in 1 each, and fistula in 2. Onlays were more likely to result in stricture than tube grafts (6 of 14 cases versus 1 of 16, p = 0.034). CONCLUSIONS: The complication and reoperation rates of buccal mucosal grafts are 57% and 33% at 5 years of followup. Changes in meatal design and temporary postoperative meatal dilation have improved the outcome in the last 5 years. Buccal mucosa remains a good choice in patients who require extragenital skin for urethral reconstruction.

    Title Abnormal Germ Cell Development in Cryptorchidism.
    Date September 2001
    Journal Hormone Research
    Excerpt

    BACKGROUND: Previous studies suggest that two fundamental, probably androgen-dependent, steps in maturation of germ cells normally occur in the prepubertal testis: the disappearance of gonocytes (the fetal stem cell pool) and the appearance of adult dark spermatogonia (the adult stem cell pool) at 2-3 months of age and the appearance of primary spermatocytes (the onset of meiosis) at 4-5 years. Previous studies of small series of cryptorchid boys suggest that both steps are defective in undescended testes and to a lesser degree in descended testes contralateral to unilaterally undescended testes. The purpose of this study is to confirm the previous findings of defective germ cell maturation in a large series of boys with unilateral undescended testes. PATIENTS: Seven hundred and sixty-seven boys with unilateral cryptorchidism who had orchidopexy and bilateral testicular biopsies between birth and 9 years of age were studied. MATERIALS AND METHODS: Total and differential germ cell counts were performed on semithin histologic sections of the biopsies. The results from the undescended and contralateral descended testes were compared using the Wilcoxon signed-rank test and the Wilcoxon-Whitney-Mann U test. RESULTS: Gonocytes failed to disappear and adult dark spermatogonia failed to appear in undescended testes under 1 year of age indicating a defect in the first step in maturation at 2-3 months resulting in failure to establish an adequate adult stem cell pool. Primary spermatocytes failed to appear in undescended testes and appeared in only 19% of contralateral descended testes at 4-5 years of age indicating a defect in the onset of meiosis. CONCLUSION: Unilaterally undescended testes fail to establish an adequate adult stem cell pool which normally occurs at 2-3 months of age and fail to establish adequate meiosis which normally occurs at 4-5 years of age. Similar but less severe changes are seen in the contralateral descended testes. Defects in the two pubertal steps in germ cell maturation are associated with reduced total germ cell counts.

    Title Hormonal Therapy for the Subfertility of Cryptorchidism.
    Date September 2001
    Journal Hormone Research
    Excerpt

    BACKGROUND: The subfertility of cryptorchidism correlates with severely reduced total germ cell counts in prepubertal testicular biopsies of undescended testes. Reduced total germ cell counts are associated with defects in the two prepubertal steps in maturation and proliferation in germ cells: first, the transformation of the fetal stem cell pool (gonocytes) into the adult stem cell pool (adult dark spermatogonia) at two to three months of age and, second, the transformation of adult dark spermatogonia into primary spermatocytes (meiosis) at 4-5 years. The defects in maturation are associated with blunting of the normal surges in gonadotropins and testosterone. Prepubertal treatment with gonadotropin-releasing hormones would theoretically trigger normal germ cell maturation and proliferation and thereby improve total germ cell counts and improve fertility. Prepubertal treatment of cryptorchidism with the GnRH analogue Buserelin has resulted in improved total germ cell counts and improved spermiograms. The purpose of this report is to describe the results of treatment of cryptorchidism with the GnRH analogue Naferelin. PATIENTS: Twelve boys with cryptorchidism, 6 unilateral and 6 bilateral, and severely reduced germ cell counts in testicular biopsies were treated with Naferelin following successful orchidopexy and bilateral testicular biopsies. Response of the total germ cell counts was assessed in follow-up bilateral biopsies within 5 months of completing the hormonal therapy. RESULTS: Eight of the 12 boys (5 of the 6 with unilateral and 3 of the 6 with bilateral cryptorchidism) showed improvement in the total germ cell counts in one or both testes. All 8 had a poor prognosis for fertility pretreatment and a good prognosis for fertility posttreatment. Of the 5 with unilateral cryptorchidism who improved, 2 showed improvement in both testes; and 3, only in the contralateral descended testes. All 3 of the boys with bilateral cryptorchidism who improved showed improvement in both testes. Testes with absence of germ cells and older patients tended to show no improvement. Of the 6 contralateral descended, 5 (83%) improved, and of the 18 undescended testes, 8 (44%) improved. CONCLUSIONS: In this preliminary study, Naferelin therapy appears to induce improvement in the total germ cell counts and the prognosis for future fertility in 75% of patients.

    Title The Decompensated Detrusor V: Molecular Correlates of Bladder Function After Reversal of Experimental Outlet Obstruction.
    Date August 2001
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Calcium ion homeostasis has a significant role in smooth muscle function. Its regulation requires complex storage and release mechanisms via ion pumps and channels located within intracellular storage sites (sarcoplasmic reticulum) and at the plasma membrane. We have previously reported a dramatic loss of the 2 major sarcoplasmic reticulum proteins sarcoplasmic endoplasmic reticulum calcium magnesium adenosine triphosphatase (SERCA2) and the ryanodine sensitive ion channel, also called the ryanodine receptor, after outlet obstruction. In our current study we investigated the correlation of the expression of these 2 major sarcoplasmic reticulum components with bladder function recovery after the reversal of outlet obstruction. METHODS AND METHODS: Standard partial bladder outlet obstruction was created in adult New Zealand White rabbits. Voiding patterns were monitored 2 and 4 weeks postoperatively, and rabbits were selected for outlet obstruction reversal based on a voiding pattern consistent with a decompensated state, as indicated by a frequency of greater than 30 voids daily and an average voided volume of less than 4 cc. Bladder biopsy was done when outlet obstruction was reversed. Voiding performance was monitored postoperatively and the animals were sacrificed 2 weeks later. Voiding patterns and muscle strip studies enabled us to define 2 functional outcome categories after reversal, namely normal versus minimally improved. Microsomal membrane protein fractions were prepared from the same bladder tissues before and after reversal, and probed by Western blot analysis for SERCA2 and ryanodine receptor expression. RESULTS: Western blot analysis revealed a major loss of SERCA2 and ryanodine receptor expression at the time of reversal and biopsy. In 65% of bladders obstruction reversal resulted in a normalized voiding pattern with a recovery of ryanodine receptor expression that was 15% to 65% of control values. In contrast, in the 35% of bladders with persistent voiding symptoms there was minimal recovery of ryanodine receptor expression. SERCA2 expression increased slightly in each group after reversal but did not differ in bladders with normalized versus improved function. CONCLUSIONS: Bladder decompensation is highly associated with a loss of sarcoplasmic reticulum function. Furthermore, the decompensated detrusor recovers function after obstruction reversal, which is associated with the recovery of these sarcoplasmic reticulum components.

    Title The Decompensated Detrusor Iv: Experimental Bladder Outlet Obstruction and Its Functional Correlation to the Expression of the Ryanodine and Voltage Operated Calcium Channels.
    Date June 2001
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Calcium ion homeostasis has a significant role in smooth muscle function. Its regulation requires complex storage and release mechanisms via ion pumps and channels located within intracellular storage sites (sarcoplasmic reticulum) and at the plasma membrane. A prominent component of the sarcoplasmic reticulum is the ryanodine sensitive ion channel which releases calcium from the sarcoplasmic reticulum into the cytosol. At the level of the plasma membrane the voltage operated calcium channel (dihydropyridine sensitive) serves to allow an influx of extracellular calcium. Our prior studies have shown a loss of sarcoplasmic endoplasmic reticulum Ca++Mg++ATPase expression following outlet obstruction. In this study we correlate ryanodine and voltage operated calcium channel protein expression with bladder function following partial outlet obstruction. MATERIALS AND METHODS: Standardized partial bladder outlet obstructions were created in adult New Zealand white rabbits, which were divided into control, sham operated and obstructed groups. Muscle strip studies further subcategorized the obstructed group into compensated (force greater than 50% of control) and decompensated (force less than 50% of control) and were correlated with in vivo determinations of voiding frequency and voided volumes. Microsomal membrane protein fractions were prepared from the same bladder tissue and were used for Western blot analysis using specific monoclonal antibodies. RESULTS: Increased voiding frequency and decreased voided volumes correlated with the definitions of compensated and decompensated. The Western blots revealed a near disappearance of ryanodine expression in the decompensated group with minimal changes in the expression of the voltage operated calcium channel. CONCLUSIONS: Bladder performance as measured in vivo and in vitro after outlet obstruction is influenced in part by smooth muscle cell ability to maintain calcium homeostasis via the sarcoplasmic reticulum. Bladder decompensation is highly associated with a loss of sarcoplasmic reticulum function with lesser changes taking place in those calcium regulatory proteins at the plasma membrane.

    Title Laser Tissue Soldering for Hypospadias Repair: Results of a Controlled Prospective Clinical Trial.
    Date May 2001
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Laser tissue soldering has been shown to provide safe and effective tissue closure by creating an immediate leak-free anastomosis with minimal scar formation. We compared the results of laser tissue soldering and conventional suturing for hypospadias repair. MATERIALS AND METHODS: A consecutive group of 138 boys 4 months to 8 years old (mean age 15 months) was divided into a standard suturing (84) and a sutureless laser (54) hypospadias repair group. Urethral repair was defined as simple (Thiersch-Duplay or Snodgrass) and complex (onlay island flap or tube) in 101 and 37 cases, respectively. Laser tissue soldering was performed with 50% human albumin solder doped with 2.5 mg./ml. indocyanine green dye using an 808 nm. diode laser at 0.5 W. In the laser group sutures were used for tissue alignment only. At surgery neourethral and penile length, operative time for neourethral construction and the number of sutures or throws were measured. Postoperatively patients were examined for complications of wound healing, stricture or fistula. RESULTS: Mean patient age, urethral defect severity, type of repair, neourethral length and stenting time plus or minus standard error of mean were not significantly different in the 2 groups. Mean operative time was a fifth as long for laser tissue soldering in simple and complex hypospadias repair compared to controls (1.5 +/- 0.1 and 5.1 +/- 0.3 versus 8.5 +/- 0.8 and 26.7 +/- 1.7 minutes, respectively, p <0.001). The mean number of sutures used for tissue alignment in the laser group for simple and complex repair was significantly less than in controls (3.0 +/- 0.2 and 8.2 +/- 0.6 versus 8.5 +/- 0.8 and 23.2 +/- 1.5, respectively, p <0.001). All patients were followed a mean of 12 months (minimum 6, maximum 22). The complication rate was 4.7% in the laser group and 10.7% in controls with fistula in 2 of 54 cases, and fistula and meatal stenosis in 7 and 2 of 84, respectively. CONCLUSIONS: These preliminary results indicate that laser tissue soldering for hypospadias repair may be performed in almost sutureless fashion and more rapidly than conventional suturing. The ease of the laser technique and the lower complication rate in the laser group indicate that laser tissue soldering is an acceptable means of tissue closure in hypospadias repair.

    Title Abnormal Testicular Histology in Michelin Tire Syndrome.
    Date March 2001
    Journal Clinical Dysmorphology
    Excerpt

    An 8-year-old male is described with Michelin tire syndrome and an abnormal testicular histology which has not previously been reported in this syndrome.

    Title The Decompensated Detrusor Iii: Impact of Bladder Outlet Obstruction on Sarcoplasmic Endoplasmic Reticulum Protein and Gene Expression.
    Date September 2000
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Regulation of calcium ion homeostasis has a significant role in smooth muscle contractility. The sarcoplasmic endoplasmic reticulum, calcium, magnesium, adenosine triphosphatase (SERCA) is a regulatory ion pump that may have a role in the functional outcome after outlet obstruction. We investigate what correlation if any existed between SERCA protein and gene expression, and the contractile properties in the same bladder. MATERIALS AND METHODS: Standardized partial bladder outlet obstructions were created in adult New Zealand white rabbits, which were divided into control, sham operated and obstructed groups. Muscle strip studies subcategorized the obstructed group into compensated (force greater than 50% of control) and decompensated (force less than 50% of control). Microsomal membrane and total RNA fractions were prepared from the same bladder tissue. Membrane proteins were used for Western blot analysis using a SERCA specific monoclonal antibody, and total RNA was assessed with Northern blot analysis. RESULTS: The relative intensities of signals for the Western and Northern blots demonstrated a strong correlation between protein and gene expression. Furthermore there was a strong association between the loss of SERCA messenger RNA and protein expression and loss of bladder function. CONCLUSIONS: Bladder contractility after outlet obstruction is influenced in part by smooth muscle cell ability to maintain calcium homeostasis via SERCA. The loss of SERCA protein expression is mediated by down-regulation in gene expression in the same bladder. These data suggest that smooth muscle ion pump gene expression is in part mechanically (pressure work) regulated.

    Title The Modern Endoscopic Approach to Ureterocele.
    Date March 2000
    Journal The Journal of Urology
    Excerpt

    PURPOSE: During the last 20 years the surgical approach to ureterocele has evolved from major open surgery to minimally invasive endoscopic puncture. We believe that the endoscopic approach decreases the need for open surgical procedures. We identified specific factors that predict the need for repeat surgery. MATERIALS AND METHODS: We reviewed the charts of 60 new patients with ureterocele treated with primary endoscopic incision between 1991 and 1995. Followup ranged from 4 to 62 months (mean 20). Mode of presentation, ureterocele location, associated vesicoureteral reflux and association of the ureterocele with a duplex system were evaluated. Ureterocele wall thickness was assessed subjectively via radiographic and cystoscopic methods, and categorized as thin, intermediate and thick. RESULTS: All 9 patients with a single system ureterocele had an intravesical ureterocele. No patient had associated reflux nor did any require a secondary open procedure. In 3 cases new onset ipsilateral reflux into the ureterocele spontaneously resolved. Of the 51 patients with a duplex system and associated ureterocele 19 (37%) required a secondary open procedure. The ureterocele was intravesical and ectopic in 22 (43%) and 29 (57%) cases, respectively. Reflux was associated with the ureterocele in 27 patients (53%), and 12 (44%) required a secondary open procedure. A total of 11 patients underwent ureteral reimplantation of 15 refluxing renal units and only 2 renal units required ureteral tapering. Reflux is no longer present in 14 of the 15 renal units (93%). Patients with a thick walled ureterocele required repeat puncture more frequently than those with a nonthick ureterocele. CONCLUSIONS: With the use of modern endoscopic techniques children with intravesical and single system ureteroceles require secondary open surgery less frequently than those with ectopic and duplex system ureteroceles. The mode of presentation does not predict the need for a repeat open procedure. Thick walled ureteroceles require repeat endoscopic puncture more frequently than thin and intermediate walled ureteroceles.

    Title Ectopic and Undescended Testes: 2 Variants of a Single Congenital Anomaly?
    Date March 2000
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We compared pathological findings in ectopic and undescended testis to determine whether the pathological evidence supports the hypothesis that the 2 conditions are variants of the same congenital anomaly. MATERIALS AND METHODS: We identified 24 boys with ectopic testis not in the superficial inguinal pouch of Denis Browne. Seven boys were excluded from study due to unavailable clinical records for 3, contralateral undescended testis in 2 and inadequate biopsy specimens in 2. Pathological findings of ectopic testis in the remaining 17 patients were compared with those of age matched patients with unilateral undescended testis. Total germ cell count, testicular volume, patency of the processus vaginalis and epididymal abnormalities were compared. Data were analyzed using the Wilcoxon matched pairs signed rank and Fisher's exact tests. RESULTS: No difference was noted in total germ cell count (p = 0.33), testicular volume (p = 0.1475), processus vaginalis patency (p = 0.0854) or epididymal abnormalities (p = 1.00) in the 2 groups. Of the 24 boys (8%) with ectopic testis 2 also had a contralateral undescended testis. CONCLUSIONS: Similar pathological findings in ectopic and undescended testes as well as the association of ectopic testis with a contralateral undescended testis suggest that ectopic and undescended testes are variants of the same congenital anomaly. Thus, boys with ectopic testis may have an increased incidence of subfertility and testicular malignancy. This spectrum of abnormal testicular position, and its range of pathological conditions and complications may appropriately be called the undescended testis sequence.

    Title Testicular Volume Does Not Predict Germ Cell Count in Patients with Cryptorchidism.
    Date February 2000
    Journal The Journal of Urology
    Excerpt

    PURPOSE: A germ cell count of less than 0.2 germ cell per tubule on the prepubertal biopsy of cryptorchid testes predicts abnormal spermiograms and decreased fertility in adulthood, and may be used to select patients for post-orchiopexy hormonal therapy. Testicular volume directly correlates with testicular function and spermiogenesis. We determined whether testicular volume would predict the total germ cell count accurately enough to replace testicular biopsy in the modern management of cryptorchidism. MATERIALS AND METHODS: At our hospital 723 patients younger than 9 years with cryptorchidism (unilateral in 619 and bilateral in 104) underwent orchiopexy and bilateral testicular biopsies. These patients had not undergone groin surgery or hormonal therapy previously and had at least 50 tubules in each testicular biopsy. Testicular volume and position, patient age and germ cell counts were analyzed. The generalized estimating equation was used to determine whether a correlation existed between testicular volume and germ cell count. RESULTS: The generalized estimating equation demonstrated a direct correlation between testicular volume and germ cell count. However, germ cell counts predicted from testicular volume varied widely within the 95% confidence intervals. Testes with less than 0.2 germ cell per tubule cannot be reliably distinguished from those with greater than 0.2 germ cell per tubule. CONCLUSIONS: Testicular volume does not accurately predict the germ cell count in patients with undescended testes, cannot be used to select patients for post-orchiopexy hormonal therapy and cannot replace testicular biopsy in the modern management of cryptorchidism.

    Title The Role of Renal Salvage Procedures for Bilateral Wilms Tumor: a 15-year Review.
    Date January 2000
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We reviewed our experience with renal salvage procedures in patients with bilateral Wilms tumor to determine the clinical outcome. MATERIALS AND METHODS: From 1982 to 1997, 23 children with bilateral Wilms tumor were treated with partial nephrectomy at our institution, including 7 who were also treated with brachytherapy. Medical history, use and response to chemotherapy and brachytherapy, operative records, renal function, pathological results, survival, and techniques for partial and repeat nephrectomy and brachytherapy were reviewed. RESULTS: We treated 8 boys and 15 girls, of whom 21 who presented with synchronous bilateral Wilms tumor underwent primary chemotherapy followed by secondary partial nephrectomy. A total of 44 partial nephrectomies were performed and brachytherapy was done in 7 patients. Ten children have normal renal function and no disease, 10 are dead and 2 have metastatic disease. Anaplasia was the most significant factor associated with an unfavorable outcome (p = 0.003). Of the patients who were cured 60% had a positive response to initial chemotherapy compared with only 25% who had an unfavorable outcome (p = 0.09). No significant differences were noted with respect to gender, age at presentation, highest local tumor stage at presentation or initial nephrectomy. No patient treated with brachytherapy had local recurrence. CONCLUSIONS: Preoperative chemotherapy followed by nephron sparing surgery is indicated in patients with bilateral Wilms tumor, while in those with diffuse anaplasia nephron sparing surgery is contraindicated. Brachytherapy should be considered for treating local disease involving chemoresistant tumors.

    Title Calcium Ion Homeostasis in Urinary Bladder Smooth Muscle.
    Date January 2000
    Journal Advances in Experimental Medicine and Biology
    Title Biochemical and Physiological Characterization of the Urinary Bladder in Ehlers-danlos Syndrome.
    Date January 2000
    Journal Advances in Experimental Medicine and Biology
    Title Prognostic Factors for Long-term Renal Function in Boys with the Prune-belly Syndrome.
    Date October 1999
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Renal failure develops in 25 to 30% of patients with the prune-belly syndrome. The clinical parameters associated with renal failure in this condition are not well understood. We determined which factors predict renal failure in children with the prune-belly syndrome. MATERIALS AND METHODS: We reviewed the records of 35 patients with the prune-belly syndrome who were treated at our hospital during a 37-year period. Nadir serum creatinine, time to nadir creatinine, presence or absence of a patent urachus, presence and severity of urinary tract infection, and renal failure were analyzed. RESULTS: Mean followup was 14 years 2 months. In 2 of the 17 patients with a nadir serum creatinine of less than 0.7 mg./dl. renal failure developed. Each of these 2 children also had clinical pyelonephritis and urosepsis. In 12 of the 13 patients nadir serum creatinine greater than 0.7 mg./dl. strongly predicted renal failure. Nonfebrile urinary tract infection within the first year of life was not predictive of outcome (p = 0.8) but a history of clinical pyelonephritis correlated with eventual renal failure (p<0.001). Urosepsis also correlated with renal failure (p = 0.008). Children with at least 1 normal kidney on renal ultrasound or renal scan had a significantly lower chance of renal failure (p<0.001). CONCLUSIONS: Bilaterally abnormal kidneys on ultrasound or renal scan, a nadir serum creatinine of greater than 0.7 mg./dl. and clinical pyelonephritis are prognostic for renal failure.

    Title Aphallia As Part of Urorectal Septum Malformation Sequence in an Infant of a Diabetic Mother.
    Date May 1999
    Journal American Journal of Medical Genetics
    Excerpt

    A male patient with aphallia, anal stenosis, tetralogy of Fallot, multiple vertebral anomalies including sacral agenesis and central nervous system (CNS) malformations was born after a pregnancy complicated by poorly controlled maternal diabetes. Aphallia is an extremely rare abnormality and can be part of the urorectal septum malformation sequence (URSMS). While aphallia has not been reported in infants of diabetic mothers, urogenital malformations are known to occur with increased frequency. Two female products of pregnancies complicated by diabetes presented with multiple malformations including anal atresia and recto-vaginal fistula consistent with the diagnosis of URSMS. The three patients share CNS, cardiac, and vertebral anomalies, abnormalities secondary to abnormal blastogenesis and characteristic of diabetic embryopathy. URSMS is also caused by abnormal blastogenesis. Therefore, this particular malformation should be viewed in the context of the multiple blastogenetic abnormalities in the cases reported here. The overlap of findings of URSMS in our cases with other abnormalities of blastogenesis, such as VATER association or sacral agenesis is not surprising, as these associations are known to lack clear diagnostic boundaries.

    Title Mechanisms of Bladder Smooth-muscle Hypertrophy and Decompensation: Lessons from Normal Development and the Response to Outlet Obstruction.
    Date February 1999
    Journal World Journal of Urology
    Title Comparison of Dermal and Epithelial Approaches to Laser Tissue Soldering for Skin Flap Closure.
    Date September 1998
    Journal Lasers in Surgery and Medicine
    Excerpt

    BACKGROUND AND OBJECTIVE: Prior studies of laser tissue soldering (LTS) of epithelial skin have shown poor wound strength in the short-term; however, we hypothesize that greater tensile strength and healing properties will result from directing laser energy to the dermal aspect of the skin. The current study compares wound strength and histology in a rat skin flap model of epithelial and dermally applied LTS. STUDY DESIGN/MATERIALS AND METHODS: Skin flaps (2.5 x 4 cm) were raised and bisected on the dorsum of Sprague-Dawley rats. The center line of bisection was closed from a dermal approach by LTS (LTS-D, diode laser 15.9 W/cm2 + Columbia solder), the upper incision by epithelial LTS (LTS-E), and the lower incision by suturing (7-0 Vicryl). Wound skin strips (1-2 mm x 10 mm) were studied immediately (N = 14) and at 3 (N = 57), 7 (N = 31), and 10 (N = 28) days postoperatively and were subjected to tensiometric analysis. Histologic staining with hematoxylin and eosin and Mallory's trichrome methods were used to define wound architecture. RESULTS: No wound dehiscences were noted in any group. Greater immediate tensile strength was noted in wounds closed by LTS-D (521 +/- 61 g/cm2) versus LTS-E (342 +/- 65 g/cm2); however, this difference was not statistically significant (P = .08). By 3 days, both LTS-D (476 +/- 55 g/cm2) and LTS-E (205 +/- 37 g/cm2) maintained their initial strength; however, LTS-D and sutured (436 +/- 49 g/cm2) wounds were stronger (P < .05) than LTS-E. At 7 and 10 days, LTS-D (2,433 +/- 346 g/cm2 and 3,100 +/- 390 g/cm2) showed superior tensile strength (P < .05) compared to both LTS-E (1,542 +/- 128 g/cm2 and 2,081 +/- 219 g/cm2) and suturing (1,342 +/- 119 g/cm2 and 1,661 +/- 115 g/cm2). Histologic analysis of LTS-D wounds at 3 days showed full-thickness tissue apposition, complete epithelialization, and minimal inflammation or thermal injury. At 7 days, solder was present in the wounds. In contrast, LTS-E wounds at 3 days displayed lack of epithelialization secondary to thermal injury and partial-thickness tissue apposition. However by 7 days, epithelialization was complete with moderate scarring, and no solder was seen. Sutured samples appeared similar to LTS-D, except for poorer tissue apposition at the hypodermis. CONCLUSION: Our results show that skin flap wound healing after dermal LTS is superior to epithelial LTS and emphasizes the importance of site specificity in the utilization of this operative technique in reconstructive surgery.

    Title Giant Hyperplastic Nephrogenic Rest in a Solitary Kidney Presenting As an Angiomyolipoma in a Child.
    Date June 1998
    Journal The Journal of Urology
    Title Surgical Management of the Nonpalpable Testis: the Children's Hospital of Philadelphia Experience.
    Date April 1998
    Journal The Journal of Urology
    Excerpt

    PURPOSE: The management of the nonpalpable testis permits an individualized operative approach. We analyze the results of surgical management of a large series of patients with a nonpalpable testis. MATERIALS AND METHODS: Between January 1986 and June 1994 we treated 1,866 boys with undescended testes. There were 447 testes (24%) that were not palpable at presentation. Intra-operative data on these patients were collected for age at presentation, bilateral testes position, testicular size, associated inguinal anomalies (vas, epididymis and processus vaginalis) and surgical approach. For intra-abdominal testes postoperative results of 2 surgical techniques, the Fowler-Stephens procedure and Koop orchiopexy (retroperitoneal mobilization of spermatic vessels and vas) were compared in 76 patients with at least 18 months of followup. RESULTS: Average patient age at presentation was 34 months with 63% presenting before age 48 months. Of the impalpable testes 58% were on the left side, 35% were on the right side and 7% were bilateral. At operation 181 testes (41%) were atrophic or absent, 91 (20%) were intra-abdominal with 14 (3.1%) bilateral, 136 (30%) were in the inguinal canal and 39 (9%) were in other locations, including 22 at the pubic tubercle, 2 in the upper scrotum, 13 in the superficial inguinal pouch and 2 in the perineum. Of the intra-abdominal group associated extratesticular malformations were identified in 36 cases (39%). Attachment of the vas deferens to the testis was abnormal in 23 of 64 cases (36%), including 10 that were completely detached and 13 with head or tail attachment only. Of the 91 evaluable cases in the intra-abdominal group 38 (42%) had been treated with the Fowler-Stephens repair (5 in 2 stages), 33 (36%) with inguinal orchiopexy and intraperitoneal dissection without dividing the spermatic vessels, 5 with 2-stage procedures and vessel preservation and 14 (15%) with orchiectomy. One testis was left in situ. The inguinal approach with intraperitoneal extension was successful in defining the testis location or blind-ending vas and vessels in 100% of the cases. A single operation to perform orchiopexy was successful in 92% of the cases. Overall, results were considered excellent or acceptable in 32 of 33 cases (97%) after Koop orchiopexy and 28 of 38 (74%) after the Fowler-Stephens orchiopexy. CONCLUSIONS: Nonpalpable testes accounted for 24% of the patients presenting with undescended testes. At surgical exploration 39% of impalpable testes were distal to the external inguinal ring, 41% were atrophic or absent and 20% were intra-abdominal. All cases were treated through a standard inguinal incision. These data provide evidence that the inguinal approach to orchiopexy with transperitoneal mobilization of the vas and vessels without transection is highly successful for the intra-abdominal cryptorchid testis and, to date, is the preferred technique for the management of the intra-abdominal undescended testis.

    Title Laser Soldering Technique for Sutureless Urethral Surgery.
    Date October 1997
    Journal Techniques in Urology
    Excerpt

    Investigators have attempted sutureless surgery to decrease operative time, lessen the inflammatory response, maintain luminal continuity, and increase the ease of performing technically difficult surgery. Only recently has laser-tissue welding (LTW) been used for urologic reconstruction in humans. Herein, we present our technique of laser soldering with the half-watt diode laser and wavelength matched albumin-based solder. Our methodology of LTW relies on bonding between the outer surface of the wound edges and the solder. The 808-nm diode wavelength does not penetrate deep tissue, and thus relies on indocyanine green dye to localize photon absorption. Since 1994, we have performed LTW, as an adjunct to suturing (N = 25) and as a primary means of tissue closure (N = 11). Preoperative diagnoses included hypospadias, urethral stricture, urethral diverticulum, and urethral fistulae. Follow-up ranged between 3 months and 3 years to identify complications of wound healing, stricture, and fistula formation. In the 37 patients undergoing urethral surgery, no strictures or diverticula have resulted. None of the patients have had wound infections or poor wound healing. Overall, five patients have developed fistulas between 2 weeks and 6 months postoperatively. The location of the hypospadiac meatus was scrotal or penoscrotal in four of these patients. Two fistulas developed following sutureless urethroplasty (reoperative) after traumatic catheterization for urinary retention (one case for inadvertent catheter removal). In our initial experience, the overall complication rate using laser soldering was 19% compared to 24% in an historical control group. Half of the complications occurred in a reoperative situation. More recently, the overall fistula rate was 14%; however, for primary cases, the current fistula rate is only 6%. LTW is safe and easy to perform. The application of protein solders (+/-chromophores) have permitted far greater tensile strengths to be achieved than laser alone. Temperature-control and chromophore-control have permitted safety and efficacy to be achieved. Solder application site and technique are equally important in the success of the LTW process. A randomized, prospective study comparing LTW to suturing is ongoing.

    Title Partial Bladder Outlet Obstruction in the Fetal Rabbit.
    Date September 1997
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We developed and tested an animal model of bladder dysfunction due to posterior urethral valves using partial outlet obstruction of the fetal rabbit bladder. MATERIALS AND METHODS: Partial bladder outlet obstruction of fetal rabbit bladders was created on day 23 of gestation. Of the litter of 8 to 10 fetuses half was obstructed and the remainder served as controls. The doe and fetuses were sacrificed on day 30 of gestation (full term 31 to 32 days) and the fetal bladders were removed. Bladders that had doubled in weight from the average bladder weight of the control littermates were deemed sufficiently obstructed. Hematoxylin and eosin staining was performed and bladder strip response to 32 Hz. field stimulation, 200 microM. bethanechol and 200 mM. potassium chloride was measured. RESULTS: Average body weight did not differ between the control and obstructed fetuses, indicating that surgery did not hinder fetal development. Hematoxylin and eosin staining confirmed smooth muscle cell hypertrophy and increased connective tissue in the obstructed bladders. Obstructed bladder strips responded significantly less to field stimulation, and significantly more to bethanechol and potassium chloride (mean plus or minus standard deviation 5.18 +/- 1.52, 6.29 +/- 1.3 and 10.15 +/- 2.18 x force per/100 mg. tissue, respectively)than control bladder strips (9.0 +/- 1.19, 3.5 +/- 0.46 and 6.16 +/- 1.33 x force per/100 mg. tissue, respectively) suggesting that denervation supersensitivity may have resulted from obstruction. CONCLUSIONS: Partial outlet obstruction of the fetal rabbit bladder results in bladder hypertrophy and dysfunction but these changes are markedly different from those in the adult rabbit. Since rabbit fetal development is delayed compared to human fetal development, this model can be used to assess the consequences of posterior urethral valves.

    Title The Operative Management of Recurrent Ureteropelvic Junction Obstruction.
    Date September 1997
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Surgical repair of ureteropelvic junction obstruction is successful in 98% of cases. We evaluated children undergoing repeat pyeloplasty and discuss the etiology of recurrent ureteropelvic junction obstruction, surgical approach and outcome. MATERIALS AND METHODS: Between 1982 and 1996, 366 children with ureteropelvic junction obstruction were surgically treated at our institution, including 16 who presented with recurrent ureteropelvic junction obstruction and required surgery. RESULTS: Repeat repair was successful in all 16 patients, including ureterocalicostomy in 3 and dismembered pyeloplasty in the remainder. No nephrectomy was necessary. Anteriorly elongated flank incisions were made in all cases. Dense scar tissue around and obstructing the ureteropelvic junction was noted in the majority of cases. In 7 patients a redundant pelvis resulted in a kink at the ureteropelvic junction. A nephrostomy tube was placed in all cases and an additional transanastomotic stent was used in all but 2. Obstruction was relieved with 1 operation. CONCLUSIONS: A redundant pelvis resulting in a kink at the ureteropelvic junction may contribute to a higher change of urinary leakage and subsequent obstructive scar formation in cases of failed pyeloplasty. Before repeat surgery anatomy should be precisely identified by antegrade and retrograde studies. The surgical approach usually involves identifying the ureter below the area of the previous surgery and then ensuring a tension-free anastomosis. If inadequate ureteral length or an intrarenal pelvis precludes direct anastomosis, ureterocalicostomy is an alternative. A nephrostomy tube and transanastomotic stent are advisable. Nephrectomy is rarely necessary and a good functional result can be anticipated.

    Title Skin Flap Closure by Dermal Laser Soldering: a Wound Healing Model for Sutureless Hypospadias Repair.
    Date September 1997
    Journal Urology
    Excerpt

    OBJECTIVES: Laser tissue soldering (LTS) with the diode laser and human albumin-hyaluronate-indocyanine green solder is a safe and effective method of providing an immediate leak-free closure during hypospadias repair. In this report, we compare the physiology, histology, and immunohistochemistry of wound healing following LTS and suturing in a rat skin flap model. METHODS: A 4 x 5-cm skin flap was raised and bisected (4 cm) on the dorsum of 48 Sprague-Dawley rats. The central wound was either closed from a dermal approach by suturing or LTS or left open, and studied at 0, 3, 5, 7, 10, 14, and 21 days postoperatively. An intraoperative comparison was made between suturing and LTS with respect to operative time. Postoperatively, flaps were excised for tensiometric analysis, and sections were stained with hematoxylin-eosin to define wound architecture. Resting skin temperature, laser exposed temperature without solder, and maximum temperature with solder (one drop) were measured at the level of the deep dermis, superficial striated muscle layer, and within the solder. Mean peak temperatures were recorded during a 1-minute laser activation time. RESULTS: Mean continuous suturing time (4.9 +/- 1.1 minutes) was significantly (P < 0.001) faster than either LTS (7.7 +/- 0.77 minutes) or discontinuous suturing (8.2 +/- 0.62 minutes). Two seromas (sutured) and two instances of partial wound dehiscence (1 sutured, 1 LTS) were noted. Tensile strength was increased significantly (P < 0.001) for up to 5 days in the LTS group, but was equal to suturing at 7 and 10 days. Immediate tensile strength after LTS was equivalent to a 7-day healed wound. At 14 days, wounds initially left open and those closed by LTS were stronger than sutured wounds (P < 0.05). There was no evidence of thermal injury or foreign body reaction in the LTS group. Solder was incorporated within the dermis in all wounds at 21 days. Laser activation of solder resulted in significant increases in temperature at all three tissue levels: 65.0 +/- 5.2 and 69.9 +/- 6.8 degrees C in the deep and superficial skin (no significant difference between the two), and 101 +/- 15.6 degrees C within the solder (P < 0.001 versus superficial and deep skin). CONCLUSIONS: Our results indicate that sutureless dermal LTS of skin flaps provides increased tensile strength for up to 7 days, with relatively greater tensile strength provided within the first 3 days. Our laser technique does not appear to alter the normal wound healing process. Rather, solder-tissue interaction initially, and extracellular matrix infiltration of solder later, provide the basis for improved wound strength. For hypospadias repair using skin flaps, these wound attributes may permit sutureless surgery.

    Title Compliance of the Obstructed Fetal Rabbit Bladder.
    Date August 1997
    Journal Neurourology and Urodynamics
    Excerpt

    We evaluated compliance in the developing bladder using a newly developed animal model of posterior urethral valves: partial infravesical obstruction in the fetal rabbit bladder. Partial bladder outlet obstruction was created in fetal rabbits at day 23 of a 31 to 32-day gestation period. An in vitro whole bladder preparation provided data on compliance and an isolated bladder strip preparation provided data on the mechanical properties of the bladder wall. In addition, the influence of calcium on both preparations was evaluated. Partial bladder outlet obstruction in the fetal rabbit resulted in a markedly larger bladder weight (246.4 +/- 22.3 mg, n = 14) than control bladders (90.2 +/- 5.7 mg, n = 13). Isolated smooth muscle strips from obstructed and normal bladders revealed identical stretch-stress patterns. In contrast, obstructed bladders had significantly increased compliance in the whole bladder preparation. Since the increase in compliance was not correlated to mechanical properties of the isolated bladder strips, it must therefore result from the pattern of mass increase of the whole bladder wall. During filling, both the control and obstructed bladders had the same slow, large amplitude spontaneous contractions. In addition, both had rapid contractions: those in the obstructed bladders had significantly lower frequency and higher amplitude than the ones in the control bladders. Removing the calcium from the organ bath eliminated the spontaneous contractions but did not change the baseline pressure or force values, indicating that the compliance of these fetal rabbit bladders is a function of the passive properties of the bladder wall. Three main patterns occur in cystometrograms of patients with posterior urethral valves: myogenic failure, hyperreflexic bladders, and low compliance bladders. Using our model of partial outlet obstruction in the fetal rabbit bladder, we could not imitate the group with low compliance. We therefore hypothesize that the different patterns of bladder dysfunction associated with posterior urethral valves are due to infravesical obstruction occurring with different severities or at different ages of gestation.

    Title Contractile Protein Changes in Urinary Bladder Smooth Muscle During Obstruction-induced Hypertrophy.
    Date August 1997
    Journal Scandinavian Journal of Urology and Nephrology. Supplementum
    Title Lateral Meningocele Syndrome: Three New Patients and Review of the Literature.
    Date July 1997
    Journal American Journal of Medical Genetics
    Excerpt

    One female and two male patients with multiple lateral meningoceles are presented. They do not have neurofibromatosis or Marfan syndrome and share findings with the two previously described patients with multiple lateral meningoceles. The original report by Lehman et al. [1977: J Pediatr 90:49-54] was titled "familial osteosclerosis," because osteosclerosis was present in the proposita and her mother; the patient described by Philip et al. [1995: Clin Dysmorphol 4:347-351] also had increased bone density of the skull base and the sutures. Thickened calvaria were present in one of our patients; two had a prominent metopic suture. Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males. In addition, our patients showed ligamentous laxity, keloid formation, hypotonia, and developmental delay. A short umbilical cord was noted in two patients. One had a hypoplastic posterior arch of the atlas and an enlarged sella, as reported by Lehman et al. [1977]. Our patients appear to have the same syndrome as previously reported. We suggest it be called "lateral meningocele syndrome," because of this unique finding.

    Title Properties of Ca2(+)-mg2+ Atp-ase in Rabbit Bladder Muscle and Mucosa: Effect of Urinary Outlet Obstruction.
    Date July 1997
    Journal Neurourology and Urodynamics
    Excerpt

    The contractile response of the smooth muscle of the urinary bladder is dependent upon both the entrance of extracellular calcium through receptor-operated calcium channels and the stimulated release of calcium from the sarcoplasmic reticulum. In addition, partial outlet obstruction induces marked alterations in the utilization of intracellular calcium. Although calcium ATP-ase provides the energy for the translocation of intracellular free calcium into storage sites within the sarcoplasmic reticulum, very little is known about the properties of this enzyme in bladder muscle and mucosa. As an initial study, divalent ion specific ATP-ase activity was measured in extracts of rabbit bladder muscle and mucosa from control animals and from rabbits following partial urinary outlet obstruction. In both normal bladder muscle and mucosa, magnesium and calcium ions were equally effective in activating the enzyme. Seven days following partial urinary outlet obstruction, the ATP-ase activity in both bladder muscle and mucosa was significantly depressed by over 70%. The degree of the decreased enzyme activities observed within the muscularis and mucosa would indicate that specific membrane functions supported by divalent-ion-ATP-ase are dysfunctional. This hypothesis is supported by marked alterations in the utilization of intracellular calcium following partial outlet obstruction and the marked dysfunctions in both mucosal permeability and bacterial adherence to mucosa observed following partial outlet obstruction.

    Title Effect of Thapsigargin on the Contractile Response of the Normal and Obstructed Rabbit Urinary Bladder.
    Date December 1996
    Journal Pharmacology
    Excerpt

    Excitation-contraction coupling is achieved by translocation of calcium from the extracellular space as well as by the release of calcium from intracellular stores. Thapsigargin has been shown to selectively block the sarcoplasmic Ca-ATPase, thereby preventing the reuptake of calcium into intracellular stores and the participation of these calcium storage sites in the contractile response to stimulation. The current study determined the effect of thapsigargin on the contractile response to field stimulation, bethanechol, and KCl in control rabbit bladders and bladders obtained from rabbits subjected to partial outlet obstruction. Partial bladder outlet obstruction resulted in a marked increase in bladder mass and in significant decreases in the contractile response to field stimulation, bethanechol, and KCl. Thapsigargin (5-40 microM) had no effect on the contractile responses of bladder strips isolated from control rabbits to field stimulation, bethanechol, or KCl. However, bladder strips isolated from obstructed rabbits showed a significant concentration-dependent decrease in the contractile response to field stimulation in the presence of thapsigargin. Thapsigargin had no effect on the contractile responses of bladder strips isolated from obstructed rabbits to either bethanechol or KCl. In general, the data described in this study support our current hypothesis: as smooth muscle cells enlarge (hypertrophy) and the cell volume increases, there is an increased dependence on the release of intracellular calcium from the sarcoplasmic reticulum to mediate the contractile response to field stimulation.

    Title 10-year Experience with Prenatal Intervention for Hydronephrosis.
    Date September 1996
    Journal The Journal of Urology
    Excerpt

    PURPOSE: We evaluated clinical outcomes after attempted prenatal intervention in fetuses with hydronephrosis. MATERIALS AND METHODS: We retrospectively reviewed the histories of 10 fetuses considered for prenatal intervention between 1984 and 1993. One female and 8 male fetuses had bilateral hydroureteronephrosis and profound or progressive oligohydramnios, and 1 male fetus had massive progressive unilateral hydronephrosis. RESULTS: Shunt placement was not recommended and it was refused by the parents in 1 case each. Amniotic shunting was attempted in 8 fetuses between 22 and 28 weeks of gestation. Shunts were successfully placed with decreased hydronephrosis and increased amniotic fluid volume in 4 cases, while shunt placement was not technically possible in the remainder. Two shunts that retracted intra-abdominally at birth required laparotomy for retrieval. Postnatally all patients with shunts had compromised renal function. Of the 4 patients in whom attempts were unsuccessful 3 had mildly diminished renal function and 1 died of nonrenal causes (intraabdominal sepsis) on day 16 of life. No patient with a functioning shunt had postnatal pulmonary problems, whereas 3 without successful intervention had mild respiratory compromise. CONCLUSIONS: No definite advantage was noted in the small number of fetuses that underwent successful shunting. Successful shunt placement did not prevent renal insufficiency. The relief of oligohydraminos may benefit pulmonary function in some patients. The high technical failure and complication rates of in utero intervention should be considered before proceeding.

    Title The Decompensated Detrusor I: the Effects of Bladder Outlet Obstruction on the Use of Intracellular Calcium Stores.
    Date August 1996
    Journal The Journal of Urology
    Excerpt

    PURPOSE: As in other smooth muscle groups, extracellular calcium influx as well as the release of calcium from intracellular storage sites or sarcoplasmic reticulum occur in response to receptor stimulation. The relative participation of extracellular influx versus intracellular release has recently been shown to be influenced by developmental stage and obstruction. Partial bladder outlet obstruction results in marked hypertrophy of the bladder and produces alterations in contractile function. To understand better how this contractile dysfunction after outlet obstruction is influenced by intracellular calcium handling we tested the effects of 2 drugs with known effects on the sarcoplasmic reticulum. MATERIALS AND METHODS: We evaluated ryanodine, which blocks the release of calcium from the sarcoplasmic reticulum, and thapsigargin, which blocks the ability of the sarcoplasmic reticulum to pump cytosolic calcium back into the storage sites. Rabbit bladders were obstructed for different periods, after which detrusor muscle strips were harvested and contractile performance was evaluated in the absence and presence of ryanodine and thapsigargin. RESULTS: In the early phases of outlet obstruction the release of intracellular calcium increased significantly. With prolonged obstruction and detrusor decompensation the intracellular storage sites lost the ability to contribute to the generation of contractile force. CONCLUSIONS: Alterations in the calcium handling ability of the smooth muscle cell appear to have an important role in the process of decompensation of bladder function in infravesical obstruction.

    Title The Decompensated Detrusor Ii: Evidence for Loss of Sarcoplasmic Reticulum Function After Bladder Outlet Obstruction in the Rabbit.
    Date August 1996
    Journal The Journal of Urology
    Excerpt

    PURPOSE: While it may lack the classic morphological pattern in striated muscle systems, there is ample evidence that smooth muscle also contains sarcoplasmic reticulum. These intracellular storage sites release calcium into the cytosol to generate contractile force in response to various stimuli. A major component of the sarcoplasmic reticulum is an adenosine triphosphate dependent ion pump, which serves to drive free calcium out of the cytosol back into this intracellular reservoir. This ion pump serves to maintain the intracellular calcium storage sites, and also as a marker of the sarcoplasmic reticulum. MATERIALS AND METHODS: Muscle strip studies were performed to stratify the data into 3 major groups (controls, and compensated and decompensated obstructions) based on physiological performance. These were correlated with biochemical and molecular determinations of sarcoplasmic endoplasmic reticulum calcium, magnesium-adenosinetriphosphatase expression. RESULTS: Our results demonstrate a remarkable loss of sarcoplasmic endoplasmic reticulum calcium-adenosinetriphosphatase activity in the decompensated group and a moderate loss in the compensated group. CONCLUSIONS: These data provide molecular support for our previous physiological studies in which we demonstrated an important role for intracellular calcium storage and release with normal bladder smooth muscle function. These data strongly support our contention that contractile dysfunction in bladder smooth muscle following outlet obstruction is partially mediated by changes in the mechanisms of intracellular calcium homeostasis.

    Title Developmental Aspects of Excitation Contraction Coupling in Urinary Bladder Smooth Muscle.
    Date March 1996
    Journal Advances in Experimental Medicine and Biology
    Title Developmental Factors in the Contractile Response of Rabbit Urinary Bladder: Effect of Anoxia and Extracellular Acidosis.
    Date October 1995
    Journal Biology of the Neonate
    Excerpt

    Previous studies have demonstrated that the mechanism of excitation contraction coupling changes with normal development in rabbit urinary bladder smooth muscle. The present study was designed to determine whether there were any differences in the effects of anoxia and extracellular acidosis in response to field stimulation, bethanechol and KCl between mature (8 weeks) and neonatal (3 days) rabbit bladder smooth muscle. Bladder smooth muscle strips from mature and neonatal New Zealand White rabbits were mounted in organ baths and bathed in oxygenated Tyrode's solution. Anoxia was produced by changing the gas mixture to 95% nitrogen/5% CO2 and the effects on contractility were determined at different times after initiation of anoxia. The extracellular acidosis was produced by decreasing the buffer's NaHCO3 concentration. We conclude that bladder smooth muscle does not exhibit an age-specific ability to counteract the effects of anoxia or acidosis as is seen in the developing rabbit myocardium. Instead it appears that the purinergic mechanisms of contraction are much more sensitive to the effects of anoxia or acidosis. Neonatal bladder smooth muscle exhibits a greater drop in contractility with anoxia or acidosis at low frequency (2 Hz) field stimulation; we attribute this to the fact that neonatal bladder smooth muscle has a greater purinergic component in its response to field stimulation. These differences in the responses to anoxia and pH reflect alternate mechanisms of pharmacologic activation, and not inherent differences in the biochemistry of the maturing smooth muscle.

    Title Use of Injectable Fat to Obstruct the Urethra in Rabbits.
    Date September 1995
    Journal Neurourology and Urodynamics
    Excerpt

    Bulking agents have been injected to correct urinary incontinence for at least 15 years. The injection seeks to increase bladder outlet resistance by partially obstructing the urethra and thereby reduce urinary leakage in patients with stress urinary incontinence. Although the implant is effective and requires a shorter in-hospital stay than more traditional procedures, no ideal implant substance has been discovered. To assess the effectiveness of injected fat as a bulking agent, we injected small volumes of perivesical fat into the bladder neck in New Zealand White (NZW) rabbits and tested the effect on the bladder. In eight rabbits, we harvested perivesical fat and partially closed the urethral lumen with an initial injection. A second injection 1 month later completely closed the urethral lumen. We injected six other rabbits with similar volumes of saline as controls. Two weeks after the second injection, we measured micturition frequency, bladder weight, response to electrical field stimulation, and response to bethanecol in each group. Fat implants were present at the injection site in each case 4 weeks after the first injection. Rabbits receiving fat implants had increased micturition frequency, increased bladder weight, and increased response to bethanecol and field stimulation. Previous studies have demonstrated that these changes are characteristic of mild outlet obstruction in rabbits. Injected fat can be made to close the urethra and create bladder outlet obstruction in rabbits. The short-term success of fat as a bulking agent in this experiment is encouraging and suggests the need for longer term studies.

    Title The Ontogeny of Bladder Function in the Fetal Calf.
    Date July 1995
    Journal The Journal of Urology
    Excerpt

    Although numerous experimental studies have addressed urinary bladder physiology and pharmacology, little information is available concerning the ontogeny of bladder function. The present in vitro study describes the developmental aspects of bladder compliance, pressure generation and emptying in bovine fetuses from early second trimester to term (280 days). The results can be summarized as follows: 1) bladder compliance increased 3-fold between early second trimester and term; 2) sustained contractile response to bethanechol was present in all bladders; 3) field stimulation produced a submaximal, nonsustained contraction and an active relaxation when the field stimulus was turned off; 4) bladder emptying in response to bethanechol was nearly 100% in mid- and late-gestational bladders but was only 50% at early gestation; 5) bladder emptying in response to field stimulation was 20% to 40% for all gestational age groups; 6) field stimulated relaxation was observed only in the fetal bladder. These studies demonstrate that bladder physiology in utero is different from postnatal bladder function. The presence of a relaxant response during the fetal period may reflect a unique and significant role of the in utero bladder in protecting the upper urinary tracts from sustained increased pressure.

    Title Ontogeny of the Ryanodine Receptor in Rabbit Urinary Bladder Smooth Muscle.
    Date March 1995
    Journal Molecular and Cellular Biochemistry
    Excerpt

    Bladder smooth muscle contraction is mediated by both direct calcium entry through the cell membrane, and by calcium induced calcium release (CICR) from the sarcoplasmic reticulum (SR) storage sites. Ryanodine is a neutral plant alkaloid which binds to an ion channel located on the SR membrane. Its effects in cardiac skeletal muscle are well characterized where it inhibits the efflux of intracellular calcium stores, and thus it serves as a negative inotrope. It has also been shown that in the developing rabbit myocardium, there is a gradual increase in the expression of this ion channel. Little has been written about the expression and function of the ryanodine sensitive ion channel in smooth muscle. Recently we have shown that neonatal rabbit bladder smooth muscle is not very sensitive to ryanodine, while that from mature rabbits is extremely sensitive. This leads us to quantify the expression of the ryanodine sensitive ion channel. In this paper we demonstrate that the Kd values do not change to any significant degree with normal rabbit bladder development. However the Bmax values for 3 day, 2, 4, 6, and 8 week rabbit bladder smooth muscle are 7, 10, 15, 29, and 44 fmol specifically bound ryanodine/mg protein. The differences between the neonatal groups and the mature groups are significant (P < 0.5). This increase in ryanodine sensitive ion channel expression with normal growth would suggest that with normal maturation, the bladder smooth muscle cell acquires an increased pool of sequestered intracellular calcium. This would follow a similar pattern of development that has already been described in rabbit myocardium.

    Title Effect of Partial Outlet Obstruction on the Biphasic Response to Field Stimulation at Different Concentrations of Calcium.
    Date December 1994
    Journal Pharmacology
    Excerpt

    The contractile response of the rabbit urinary bladder smooth muscle to field stimulation is biphasic in nature consisting of an initial phasic contraction followed by a prolonged tonic contraction. The phasic contraction is mediated by a rapid rise in intracellular free calcium concentration which in turn is achieved by a combination of the entry of extracellular calcium into the cell and by the mobilization and release of calcium from intracellular storage sites. Partial bladder outlet obstruction in rabbits is associated with a marked depression of contractile function. The current experiments were designed to: (1) investigate the role of extracellular calcium in mediating the phasic and tonic components of the contractile response to field stimulation and (2) determine the effect of partial outlet obstruction on this relationship. The results can be summarized as follows: in the control bladder, increasing the extracellular calcium concentration from 0.6 to 5.4 mmol/l enhanced the phasic contractile response to a 2-Hz stimulation to a significantly greater degree than the response to a 16-Hz stimulation. Increasing the extracellular calcium concentration had no effect on the plateau phase of the contractile response. Partial outlet obstruction significantly reduced the phasic and tonic responses to all frequencies of stimulation. In general, there was a greater reduction in the tonic response to field stimulation (relative to the phasic response).

    Title Effect of Partial Outlet Obstruction of the Rabbit Urinary Bladder on Ryanodine Binding to Microsomal Membranes.
    Date November 1994
    Journal General Pharmacology
    Excerpt

    1. Partial outlet of obstruction of the rabbit urinary bladder results in a significant increase in the ability of ryanodine to inhibit field stimulated contraction. The current study determined the effect of outlet obstruction on ryanodine binding to microsomal membranes. 2. The results demonstrate: (i) Ryanodine binding is linear showing one set of ryanodine binding sites (Bmax = 28 +/- 3.5 fmol/mg protein; Kd = 4.2 nM). (ii) Total ryanodine binding was slightly increased at 1 and 3 day following obstruction. (iii) Binding increased approx 4-fold at 5 and 7 days post obstruction. (iv) No change in the Kds were noted at any time period. 3. The results of these studies indicate that smooth muscle hypertrophy secondary to partial outlet obstruction induces a marked increase in the role of intracellular calcium in the mediation of the contractile response to field stimulation.

    Title What is the Most Accurate Way to Study the Active Properties of Bladder Smooth Muscle?
    Date August 1994
    Journal Pharmacology
    Excerpt

    There is often disagreement over the optimal method by which to study the active properties of smooth muscle. While some favor setting smooth muscle strips at a resting or passive tension of 1 g, others have argued in favor of determining the Lo or optimal length for maximal force generation for each individual strip. Setting each strip to its individual Lo is tedious, especially if one is dealing with multiple strips during one experiment. Is it possible to study smooth muscle strips at an average length at which most strips of similar dimensions exhibit their maximal force, and if this method is used to what extent does it underestimate the maximal force generated? When comparing bladder, smooth muscle strips 1 cm long from pregnant versus virginal rabbits, the average length at which maximal force was generated was 2.41 and 2.45 cm, respectively (p = n.s.). Studying all strips at a length of 2.5 cm (2.5 x the slack length) would have resulted in a 10% underestimate of the maximal force within each group (p = n.s.). We conclude that comparative bladder smooth muscle strip studies can be accurately carried out at an average fixed length provided that preliminary studies are done to determine the length-tension relationships for the specific experimental situation.

    Title Primary Dilated Megaureter: Long-term Followup.
    Date July 1994
    Journal The Journal of Urology
    Excerpt

    Previously, we reported on the changing concepts in the management of 35 neonates with primary obstructive megaureters, 25 of whom were observed without surgery for a mean of 28 months while 10 were surgically treated. We report the long-term outcome of the 25 patients who were managed without surgery. This group consists of 19 male and 6 female neonates with 19 unilateral and 6 bilateral dilated ureters. Of the patients 17 presented with an antenatal diagnosis of hydronephrosis, 2 with infection and 6 with incidental findings. None of the patients had vesicoureteral reflux. Followup serial imaging (2 or more studies per case) consisted of excretory urography in 18 of the 25 cases, diethylenetriaminepentaacetic acid renal scan in 16 and/or sonogram in 10. Mean followup was 7.3 years (range 4.8 to 12.4) for 24 patients and 1 was lost to followup after 1.5 years. Excretory urography showed improvement in urinary tract dilatation in 12 cases and stable dilatation in 6. Renal scans demonstrated expected interval increases in the glomerular filtration rate with age without any deterioration in per cent of renal function in all 16 cases. None of the patients had stones, pain or pyelonephritis. We conclude that it is safe to follow a select group of patients with primary dilated megaureters in the absence of vesicoureteral reflux. We recommend antibiotic prophylaxis and serial urinary tract imaging to confirm renal growth and preservation of renal function.

    Title Developmental Aspects of Excitation Contraction Coupling of Rabbit Bladder Smooth Muscle.
    Date July 1994
    Journal The Journal of Urology
    Excerpt

    There is growing evidence that smooth muscle function changes with normal development. In this study a Scatchard analysis revealed that the binding of 3H-ryanodine changed from 6.6 fmol./mg. protein in 3-day-old rabbits to 44 fmol./mg. protein in 8-week-old rabbits (p < 0.05) with no associated developmental changes in the dissociation constants. The physiological findings using muscle strip techniques correlate well with these findings in that the neonatal bladders are far less sensitive to ryanodine than their mature counterparts. In contrast, nifedipine inhibited contractility in the neonatal group to a much greater degree than the mature group. These biochemical and physiological findings support our contention that the mechanism for excitation contraction coupling changes with normal development. Contraction in neonatal rabbit bladder smooth muscle is more dependent upon the influx of extracellular calcium and with normal maturation mechanisms for intracellular calcium storage and release begin to predominate.

    Title Bovine Bladder Compliance Increases with Normal Fetal Development.
    Date July 1994
    Journal The Journal of Urology
    Excerpt

    In this study we characterized the elastic properties of the normal bovine bladder throughout fetal life, the newborn period and into adulthood. The elasticity of the bladder was measured with a novel circularly clamped bladder testing system. Pressurization of a circularly clamped bladder tissue sample caused the tissue to deflect upward repetitively in the shape of a spherical cap. If the centerline deflection is much larger than the tissue thickness, the elastic modulus, considered the inverse of compliance, can be determined using linear regression techniques. The results of our analyses showed that the elastic modulus decreases in direct proportion with increasing gestational age. These data suggest that during normal development of the bovine fetal bladder there is a progressive change from a rather stiff noncompliant bladder characterized by a high elastic modulus to a compliant bladder with a lower elastic modulus. Moreover, the increase in compliance appears in the developmental period when urine production first occurs. These observations suggest that volume work may be a significant event in the normal development process of the bovine bladder and results in an increase in bladder compliance. Conversely, the poorly compliant fetal bladder may explain some of the transient dilatations of the upper urinary tract which have been documented in utero. Finally, from the newborn period to the mature adult bovine we documented a relatively modest increase in the elastic modulus or decrease in bladder compliance which may reflect the normal aging process.

    Title Effect of Ryanodine on the Contractile Response of the Normal and Hypertrophied Rabbit Urinary Bladder to Field Stimulation.
    Date December 1993
    Journal Pharmacology
    Excerpt

    Bladder contraction, similar to most smooth muscle contraction, is dependent on both the translocation of extracellular calcium across the cell membrane, and the calcium-stimulated release of intracellular bound calcium. Partial outlet obstruction of the urinary bladder induces a marked increase in bladder mass which results in part from a substantial hypertrophy of the smooth muscle elements. In addition, the increase in bladder mass is associated with specific contractile dysfunctions. It is not known if the contractile dysfunction induced by partial outlet obstruction is related to alterations in calcium metabolism. Ryanodine is a pharmacological tool which can be utilized to study the role of intracellular calcium in mediating contractile events. Ryanodine stimulates the loss of intracellular calcium (bound in the sarcoplasmic reticulum) and reduces the participation of intracellular calcium in the contractile response to specific forms of stimulation. The current study investigates the effect of partial outlet obstruction on the ryanodine inhibition of the contractile response of rabbit urinary bladder to field stimulation. New Zealand White rabbits were anesthetized and catheterized with an 8-french Foley catheter. A 00 silk suture was surgically placed around the catheterized urethra, the incision closed, and the catheter removed. After 1, 3, 5 and 7 days of partial outlet obstruction, the bladder was rapidly removed and utilized immediately for contractile studies. The effect of ryanodine (0-80 microM) on the peak response to 2-, 8- and 16-Hz field stimulation at 0.6, 1.8 and 5.4 mM calcium was determined.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Nonoperative Management of Blunt Pediatric Major Renal Trauma.
    Date November 1993
    Journal Urology
    Excerpt

    Although algorithms exist for the management of renal trauma in adults, guidelines have not been established in children. Of 1,175 patients entered into our Trauma Registry between 1987 and 1991, 61 (5.2%) presented with gross or microscopic hematuria. Eight of the 58 patients (13.8%) who had blunt abdominal trauma had major renal injuries. Gross hematuria (n = 10) was a significant predictor of major renal injury (n = 5) (p < 0.001). All 3 patients with microscopic hematuria and a major renal injury also had evidence of multisystem trauma. Admission blood pressure, hemoglobin, and trauma score were not predictors of major renal trauma. All cases were managed nonoperatively except for 1 patient who required a partial nephrectomy for continued hemorrhage. These data suggest that hematuria of any degree should be evaluated in the pediatric population, since major injuries can occur with even microscopic hematuria or in the absence of shock. Nonoperative management in this series resulted in no morbidity or delayed complications and suggests that surgical exploration be reserved for ongoing bleeding.

    Title Developmental Aspects of Bladder Contractile Function: Evidence for an Intracellular Calcium Pool.
    Date August 1993
    Journal The Journal of Urology
    Excerpt

    Recent studies indicate that specific functional changes in smooth muscle accompany development and that these functional differences may relate to developmental alterations in intracellular calcium content. The possibility that neonatal bladder smooth muscle might be more permeable to calcium ions was tested using the radioligand H3 PN-200 and subsequent Scatchard analyses. No differences in either receptor density or the dissociation constants were noted in comparisons between neonatal and mature rabbit bladder smooth muscle. The sensitivity to calcium in isolated bladder smooth muscle strips exposed to high potassium was tested following calcium depletion. Calcium repletion was performed and dose response curves were generated, which showed that the neonatal strips had a significantly lower effective dose producing 50% of maximal response than their mature counterparts (1.5 versus 7.5 mM., p < 0.05). These findings are consistent with the hypothesis that intracellular binding and secondary calcium release are low in neonatal bladder smooth muscle, and that they increase with maturation. These studies are also consistent with the studies showing maturational increases in the intracellular binding and storage of calcium (sarcoplasmic reticulum), which have been reported in the developing rabbit and sheep myocardium.

    Title Developmental Aspects of Bladder Contractile Function: Sensitivity to Extracellular Calcium.
    Date March 1992
    Journal Pharmacology
    Excerpt

    The urinary bladders of 1-day and 1-week-old rabbits generate higher intravesical pressures in response to bethanechol and field stimulation than bladders isolated from mature 8-week-old rabbits. Yet the density of cholinergic receptors in the rabbit bladder does not change with maturation (1 day to 8 weeks). In an effort to better understand the molecular mechanisms by which newborn rabbit bladders generate greater pressures than the bladders of adult rabbits, we studied the effect of maturation on the relationship between extracellular calcium and contraction. Our results showed quite clearly that (1) at physiologic concentrations of calcium (2.5 mumol/l), isolated bladder strips of 1-day- and 1-week-old rabbits contracted in response to bethanechol to 98% of their maximal tension as opposed to 68% for their 8-week-old counterparts, (2) the ED50 (for calcium) for the 1-day and 1-week bladders was 0.4 mmol/l whereas the ED50 for the adult bladder strips was 2.2 mmol/l, and (3) the neonatal bladders demonstrated a much greater sensitivity to diltiazem than the adult bladders. The contractile response to calcium of the neonatal bladders was significantly inhibited by 1 mumol/l diltiazem whereas the 8-week-old bladders showed no inhibition at this concentration. In a second series of experiments, the effect of extracellular calcium on concentration was correlated with the intracellular concentration of free calcium using the calcium fluoride FURA-2 and surface spectrofluorometry. These studies confirmed that the increased contractile response of the neonatal bladder strips to calcium or cholinergic agonists was associated with an increase in the maximal intracellular free calcium concentration.

    Title Effects of Pregnancy on Muscarinic Receptor Density and Function in the Rabbit Urinary Bladder.
    Date March 1992
    Journal Pharmacology
    Excerpt

    The contractile response of the rabbit urinary bladder to field stimulation consists of both cholinergic and purinergic components. In general, approximately 60% of the contractile response to field stimulation is cholinergic and 40% is purinergic. Although the purinergic response represents a significant proportion of the initial (phasic) pressure response to field stimulation of the isolated whole bladder, it contributes only 10-15% of the ability of field stimulation to empty the bladder. The current study investigates the effects of pregnancy on the contractile responses of the isolated urinary bladder to cholinergic and purinergic stimulation. The results of these studies indicate that pregnancy induces substantial changes in the physiology and pharmacology of the urinary bladder. The following data are consistent with the theory that pregnancy substantially increases the relative purinergic component of the response to field stimulation (and presumably neuronal stimulation): (1) there was a significantly greater response of the bladders isolated from pregnant rabbits to low-frequency field stimulation; (2) atropine was more effective at inhibiting the pressure generation of bladders isolated from virgin female rabbits; (3) field stimulation was more effective at emptying bladders isolated from virgin female rabbits; (4) the response of the bladders from pregnant rabbits to bethanechol was significantly reduced, whereas the response to ATP was significantly increased. In addition to these effects of pregnancy on bladder physiology, pregnancy induced a 50% decrease in the muscarinic receptor density of the urinary bladder body, which correlated very well with the 50% decrease in the contractile response to bethanechol.

    Title Development Factors in the Contractile Response of the Rabbit Bladder to Both Autonomic and Non-autonomic Agents.
    Date February 1991
    Journal Pharmacology
    Excerpt

    Previous work in this laboratory has demonstrated that the bladders of 1-day-old and 1-week-old rabbits generate higher pressures in whole-bladder preparations than bladders from mature 8-week-old rabbits. In addition, the density of cholinergic receptors does not change during this maturation period. The present study was designed to determine if the increased responsiveness of the neonatal bladder was specific for cholinergic stimulation. Using bladder strips, we have demonstrated that the newborn bladders generated much greater tension in response to ATP, serotonin, histamine, and substance P. The response of the 1-day-old bladder smooth muscle to these contractile agents was at least double the response of the 8-week-old bladders. However, the response of all age groups to bethanechol was approximately the same, and the response to KCl was only 40% greater in the 1-day-old bladders as compared to the adult. These current studies indicate that the newborn bladder responds to a variety of nonadrenergic, noncholinergic agonists to a significantly higher degree than the adult bladder, and that maturation is accompanied by substantial changes in the pharmacology of the bladder.

    Title Effect of Pregnancy on Rabbit Urinary Bladder Physiology. 1. Effects of Extracellular Calcium.
    Date February 1991
    Journal Pharmacology
    Excerpt

    Recent advances in imaging technology have allowed for the diagnosis of many congenital urologic abnormalities through the use of antenatal ultrasonography. There is controversy in the literature as to whether antenatally detected dilatations of the urinary tract are always secondary to obstruction or if in select cases the dilatations are physiologic in nature and will spontaneously regress. Benign dilatations of the fetal urinary tract are postulated to be secondary to the increased fetal diuresis and a more compliant fetal urinary tract. No one has investigated the possibility that such dilatations might be a consequence of the hormonal changes seen with pregnancy. In this study we present evidence for a change in bladder function with pregnancy. A summary of our results shows that in the presence of bethanechol, strips from the urinary bladders of pregnant rabbits generate 50% less tension in response to calcium than those from nonpregnant rabbits. Such a suppression in smooth muscle function might also help explain the benign dilatations of the upper urinary tract which are seen frequently during pregnancy.

    Title Urological Applications of Human Papillomavirus Typing Using Deoxyribonucleic Acid Probes for the Diagnosis and Treatment of Genital Condyloma.
    Date January 1989
    Journal The Journal of Urology
    Excerpt

    The use of deoxyribonucleic acid probes to examine the type of the human papillomavirus genome found in penile lesions is described at a technical level and in a clinical application. At least 40 different types of human papillomavirus have been identified and these types vary not only in their deoxyribonucleic acid base sequences but also in their clinical manifestations. Although deoxyribonucleic acid probes currently have a role only in a research setting, this study delineates the possible role of this technology in a clinical setting to detect subclinical intraurethral human papillomavirus. The results have widespread implications regarding the treatment of condyloma and the associated cervical dysplasia. In this series 25 grossly visible lesions were typed and 85 per cent contained human papillomavirus types 6 and 11. In contrast, microscopic lesions identified in the male partners of women with cervical dysplasia were shown to contain human papillomavirus types 16, 18 or 31 in 60 per cent of the cases. In addition, urethral brushings were obtained and were positive for human papillomavirus in 50 per cent of the cases despite normal urethroscopy. Human papillomavirus types 16, 18 or 31 accounted for 70 per cent of the positive urethral brushings.

    Title Results of Carbon Dioxide Laser Therapy and Topical 5-fluorouracil Treatment for Subclinical Condyloma Found by Magnified Penile Surface Scanning.
    Date July 1988
    Journal The Journal of Urology
    Excerpt

    Previously we demonstrated a 68 per cent recurrence rate for subclinical penile human papillomavirus infections found by magnified penile surface scanning and treated with the carbon dioxide laser. In this report it is shown that the addition of a regimen of adjuvant topical 5-fluorouracil does not lower the recurrence rate. This knowledge combined with the evidence for a subclinical urethral reservoir of human papillomavirus implies that any strictly topical therapy will fail at 4 months of followup and that improved systemic therapy may be needed.

    Title Bladder Calculi in Women After Urethrovesical Suspension.
    Date May 1988
    Journal The Journal of Urology
    Excerpt

    There have been a number of reports recently on vesical calculi in women with a history of gynecological procedures. Within 1 year we encountered 2 patients with vesical calculi after vesicourethral suspension performed with concomitant hysterectomy. These calculi formed on a retained intravesical suture and a monofilament knitted polypropylene pledget, and they produced interesting pathological and radiographic findings.

    Title Carbon Dioxide Laser Therapy of Subclinical Condyloma Found by Magnified Penile Surface Scanning.
    Date June 1987
    Journal Urology
    Excerpt

    The etiology and treatment of condyloma caused by the human papilloma virus (HPV) and the association of HPV with cervical dysplasia and/or carcinoma is a major issue in current gynecologic literature. This study examined results of carbon dioxide (CO2) laser treatment of 127 high-risk males with biopsy-proved subclinical HPV infections found by magnified penile surface scanning (MPSS). At a mean follow-up of four months a 66 per cent recurrence rate of microscopic condyloma was encountered. A discussion of the causes of such a high recurrence rate is given, with conclusions on this and prior condyloma treatment series.

    Title Adolescent Urologic Emergencies.
    Date
    Journal Adolescent Medicine (philadelphia, Pa.)
    Excerpt

    The vast majority of adolescent genitourinary problems are treated effectively by a general urologist once the problem is recognized by the primary care or emergency physician. Male adolescents may present with acute scrotal pain, often accompanied by swelling, which constitutes one of the few true urologic emergencies. The first step is to rule out testicular torsion because gonadal salvage depends on rapid restoration of blood flow. Other urologic problems in male and female adolescents are also addressed.

    Title Cryptorchid Testis Histopathology in Myelomeningocele Patients.
    Date
    Journal Journal of Pediatric Urology
    Excerpt

    PURPOSE: Cryptorchidism occurs in 25% of boys with myelomeningocele (MMC) compared to 3% of the general population. Testicular biopsy histopathology correlates with future sperm counts. We studied testicular histology in boys with cryptorchidism and MMC to investigate if the MMC influences histological findings. MATERIALS AND METHODS: The study group consisted of six patients with MMC and undescended testis (UDT) who underwent orchiopexy and bilateral testis biopsy. Twelve testicular biopsies from six patients were compared to 40 biopsies from 20 UDT-only controls. Total germ cell count per tubule (TGC/T) and the percentage of adult dark spermatogonia (%Ad) in undescended and contralateral descended testes from the patients were compared with controls. RESULTS: In the study group, two had total absence of germ cells (TGC/T=0) and three had severely reduced germ cells (TGC/T<0.2). Four had total absence of Ad spermatogonia and the remaining two had severely reduced Ad spermatogonia (%Ad=5). The mean TGC/T and %Ad in patients with UDT and MMC were conspicuously lower than controls. The differences did not reach statistical significance (P=0.09-0.29). CONCLUSION: These results suggest that patients with both MMC and UDT have a more severe reduction in total number and more severely delayed maturation of germ cells than do patients with UDT alone. With only six patients in this study, there was not the power to detect statistical significance. In addition to the reproductive problems due to erection and ejaculatory dysfunction in patients with MMC, this severe testicular histopathology may increase the risk of subfertility.

    Title The Bladder-brain Connection: Putative Role of Corticotropin-releasing Factor.
    Date
    Journal Nature Reviews. Urology
    Excerpt

    The coordination of pelvic visceral activity with appropriate elimination behaviors is a complex task that requires reciprocal communication between the brain and pelvic organs. Barrington's nucleus, located in the pons, is central to a circuit involved in this function. Barrington's nucleus neurons project to both pelvic visceral motorneurons and cerebral norepinephrine neurons that modulate behavior. This circuit coordinates the descending limb of the micturition reflex with a central limb that initiates arousal and shifts the focus of attention to facilitate elimination behavior. The same circuitry that links the bladder and brain enables pathological processes in one target of the circuit to be expressed in the other. Urological disorders can, therefore, have cognitive and behavioral consequences by affecting components of this circuit; and in the opposing direction, psychosocial stressors can produce voiding dysfunctions and bladder pathology. The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington's nucleus neurons, is a potential mediator of these effects.

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