Barbara Schlenck

MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity.

Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID.

Diagnosis and management of pediatric urethral injuries.

Objective: The incidence of urethral injuries in children is rare due to the fact that the urethra is short, mobile and protected by the pubic bone. The management of urethral trauma in childhood remains controversial because of the limited expertise of most urologists. Material and Methods: We performed a literature review by searching the Medline database for articles published between 1975 and 2010 based on clinical relevance. Electronic searches were limited to the keywords ‘pediatric’, ‘urethral injury’, ‘trauma’ and ‘reconstruction’. Results: Retrograde urethrography is considered the gold standard for diagnosis of urethral injuries. The initial management should ensure drainage of the bladder either by suprapubic cystostomy or urethral realignment if possible: in complete anterior urethral disruption as well as in children with life-threatening pelvic and intra-abdominal injuries after posterior urethral injuries, a deferred repair after 3 months is necessary. Immediate primary suturing of disrupted and dislocated urethral ends should be avoided because of high complication rates. Primary repair, however, of the defect is possible in girls avoiding a 2-stage approach. Conclusion: The aim of therapy is minimizing remote damages such as urethrocutaneous fistulae, periurethral diverticulae, strictures, incontinence and impotence with different therapeutic management depending on classification of the injury and the presence of life-threatening injuries.

Growth curves of the fetal prostate based on three-dimensional reconstructions: a correlation with gestational age and maternal testosterone levels

There are two papers in this section this month. The first, by authors from Austria, concerns growth curves of the fetal prostate, correlating gestational age and maternal testosterone using three‐dimensional reconstructions. The second, from the UK, investigated testicular microlithiasis, and found no convincing evidence that alone it is a premalignant condition.

Health-related quality of life in children with vesicoureteral reflux – Impact of successful endoscopic therapy

OBJECTIVES Endoscopic therapy for vesicoureteral reflux (VUR) using dextranomer/hyaluronic acid (Dx/HA) has become increasingly popular, but the subjective impact of this therapy and subsequent reflux resolution on health-related quality of life (HRQoL) remains unclear. The aim of this study was to address this issue. MATERIALS AND METHODS One hundred children (65 girls, 35 boys; mean age 4.46 years) cured of primary VUR by endoscopic treatment were retrospectively reviewed. The Glasgow childrens benefit inventory (GCBI) - a validated, reproducible, post-interventional questionnaire consisting of four subscales - supplemented by sociodemographic and disease-specific questions was employed. The HRQoL benefit was calculated on a scale ranging from -100 (complete failure) to +100 (complete success) and correlated with supplementary data. RESULTS Total response rate was 88%. Mean total GCBI score was 28.4+/-20.3 representing a significant HRQoL amelioration. All GCBI subscores improved with the physical health subscale being most relevant. A gender-specific, significant difference in relative GCBI scores was discovered. Correlation with critical life events and time since operation proved the positive effect on HRQoL to be durable. CONCLUSIONS Resolution of primary VUR secondary to Dx/HA treatment significantly improves HRQoL. HRQoL is positively affected in many areas and not only in those directly associated with VUR. These improvements are not temporary, suggesting that successful Dx/HA therapy may be superior to medical management in terms of childrens quality of life.

Extracellular Microenvironment and Cytokine Profile of the Ureterovesical Junction in Children With Vesicoureteral Reflux

PURPOSE Vesicoureteral reflux is caused by a defective valve mechanism of the ureterovesical junction. Previous studies have revealed structural and metabolic changes in the intravesical ureter, impairing its contractile properties. Smooth musculature and nerves are replaced by collagen, while matrix degrading enzymes are over expressed. We investigated the presence of regulating cytokines and the extracellular matrix composition to elucidate further the pathophysiology of vesicoureteral reflux. MATERIALS AND METHODS Ureteral endings were obtained from 28 children during antireflux surgery, and 14 age matched autopsy specimens served as controls. Routine histological sections were immunostained for insulin-like growth factor-1, nerve growth factor, transforming growth factor-beta1, tumor necrosis factor-alpha and vascular endothelial growth factor. Smooth muscle staining was supplemented by tenascin C, tetranectin and fibronectin detection. Staining patterns were investigated using computer assisted, high power field magnification analyses. RESULTS Tumor necrosis factor-alpha and transforming growth factor-beta1 were significantly more abundant in vesicoureteral reflux samples, whereas insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor were more prevalent in healthy controls. Fibronectin was intensely expressed in refluxing ureters, while it was scarce in healthy children. Tenascin C was notable within the urothelium of both groups. Only vesicoureteral reflux samples displayed tenascin C in the musculature and connective tissue. Tetranectin staining was only detected in vesicoureteral reflux. CONCLUSIONS Several cytokines are differentially expressed in primary refluxing ureters, indicating an ongoing tissue remodeling process in the ureterovesical junction region. Additionally, the smooth muscle coat is widely lacking, while extracellular matrix proteins typical for tissue shrinkage and reorganization are over expressed. These alterations are likely to contribute to the malfunctioning active ureteral valve mechanism in primary vesicoureteral reflux.

Endoscopic treatment of vesicoureteral reflux using dextranomer/hyaluronic acid copolymer in children: results of postoperative follow-up with real-time 3D sonography.

Objectives: We evaluated whether real-time 3D ultrasound (4D-US) together with clinical evaluation is an alternative to voiding cystourethrography (VCUG) after endoscopic treatment of vesicoureteral reflux (VUR) in children at postoperative follow-up. Material and Methods: We reviewed 178 children who underwent endoscopic therapy with dextranomer/hyaluronic acid copolymer in grade II or III VUR between 2002 and 2005. 4D-US was performed in all patients 1 day and 3, 9 and 18 months after endoscopic therapy. Only children with postoperative urinary tract infections (UTIs) and/or nonorthotopic position of the bulking agent were referred for VCUG. Results: In 93% of the ureteral units, the depot could be detected in the orthotopic position after 3, 9 and 18 months. None of these children developed UTIs in the postoperative follow-up. Twelve children demonstrated a shifting of the depot, indicating a possible therapy failure. Eight of these 12 patients (66.7%) presented a positive VCUG, and 50% of them sustained UTIs. Conclusions: 4D-US seems to be a sufficient protocol in the follow-up of children after endoscopic treatment of low-grade VUR. VCUG should be performed in cases of a shifted position of the depot; invasive investigations are unnecessary in asymptomatic children with orthotopic bulk.

Clinical outcome after endoscopic therapy for occult vesicoureteral reflux in females: preliminary results of a retrospective case series.

Abstract Objective. The aim of this study was to evaluate the clinical outcome after endoscopic therapy by injection of bulking agent in the treatment of occult vesicoureteral reflux (VUR) [no VUR on standard voiding cystourethrography (VCUG), but positive 99mTc-2,3-dimercaptosuccinic acid (DMSA) scan] in females who have recurrent febrile urinary tract infections (UTIs). Material and methods. A case series was retrospectively identified of 24 females (mean age 15.5 years) with negative VCUG, but renal scars in one (n = 4) or both (n = 20) kidneys on DMSA scan. Endoscopic injection was performed bilaterally in 20 (83.3%) and unilaterally in four patients (16.7%). The incidence of postoperative UTIs was documented with a mean follow-up of 2.5 years (range 1–6 years). Results. The mean renal part function (DMSA scan) on the left and right sides was 53.5% (15–74%) and 47.3% (26–85%), respectively. Twenty-one out of 24 patients (87.5%) showed no evidence of any febrile UTIs postoperatively. One patient (4.2%) experienced a further febrile UTI 6 months after treatment. Two other patients (8.3%) had one questionable afebrile UTI, 4 and 3 years after therapy. Pressure–flow electromyography confirmed a dysfunctional voiding pattern in 12 patients (50%) treated with pelvic floor therapy and behavioural interventions before endoscopic therapy. Conclusions. Injection of bulking agent seems to be a suitable treatment for occult VUR in females to prevent further febrile UTIs. Patients with occult VUR should undergo a careful evaluation of possible urodynamic disorders such as dysfunctional voiding. These findings should be studied in prospective trials before drawing any conclusions.

Dysplasia, architectural derangement, extracellular matrix degradation and regulation of Tgf-ß3 within the interureteric muscle in children with vesicoureteral reflux

Purpose The interureteric muscle represents an essential part of an adequate antireflux mechanism. Biopsies from children operated on for vesicoureteric reflux were investigated using morphological and immunohistochemical methods to evaluate smooth muscle configuration, potential muscle dysplasia and connective tissue changes in that area. Material and methods Biopsies of the interureteric muscle were obtained from 22 ureterorenal units undergoing reflux surgery. Mean age of patients was 32 months, reflux grades III to V, respectively. Routine histological paraffin embedded sections were stained -actin to evaluate the presence,α with haematoxylin, eosin and smooth muscle allocation and morphological integrity of the interurerteric smooth muscle architecture. Indirect immunohistochemical methods were used to assess the extracellular matrix for collagen composition. Extracellular matrix involvement was assessed estimating transforming growth factor- s III (TGF-s3) expression. Results All biopsies showed different grades of muscle atrophy and degradation. In these smooth muscle tissue lacking regions, disordered fibre arrangement associated with a 2 to 3-fold increase in endomysial and perimysial connective tissue in particular collagen type III was observed. Increased mesenchymal cell proliferation in the degenerated tissue areas was associated with a significant TGF-s3 expression of the surrounding muscle cells and correlated with organized collagen deposition. Conclusions Extracellular matrix remodelling with interstitial fibrosis of the longitudinal muscle sheath of the ureterovesical junction may be mediated through upregulation of TGF-s3. Diminution or even complete loss of contractile elements of the interureteric muscle in children with congenital vesicoureteral reflux is obviously associated with an inadequate antireflux mechanism of the vesicoureteral junction.

The Devloping Prostate: An Interaction Of Androgens And Estrogens

Purpose Androgens and estrogens modulate both fetal prostatic development and the pathophysiology of hyperplasia and cancer. Throughout life the exact time course of these interactions and their allocation to different prostatic compartments remain unclear. We investigated the presence and relationship of the androgen (AR) and both estrogen receptor subtypes (ER α,β) in fetuses, infants and adults. Material and methods 11 fetal, 5 infant, and 6 adult specimens were included. Histological sections of these prostates were morphologically analyzed. All specimens were double stained using anti-AR and anti-ER α antibodies. Additionally, 7 fetal and infant specimens were stained for the AR and ERβ. RT-PCR was done to verify the tissue expression of all receptors. Results ER α,β and AR were detectable starting from 12th week of gestation and in neoplastic tissue. RT-PCR clearly underlined those findings. Both types of the ER were found in the stroma and in the epithelium while the staining intensity and distribution was different. ER α was more densely expressed in the epithelium than in the stroma in all stages. ER β-reactivity was notably weaker but positive in the epithelial and stromal compartment. AR (epithelium) increased in the second trimester. Postnatally a decrease of AR-expression was detected. However, AR-staining intensity was strong in prostate cancer. RT-PCR verified the presence of all three receptors from the 12th gestational week on till 6 years of age. Conclusions This study outlines the different expression patterns of AR, as well as ER α and β in the human prostate. These findings may be helpful to characterize both normal and abnormal prostate development. The high abundance of ER α suggests a pivotal role along with the AR in the development of the fetal prostate and in prostate cancer formation. ER β is ubiquitous in all prostatic compartments and throughout different developmental stages rendering its relative importance difficult to assess.