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Because of poor mechanical strength, applications of electrospun polystyrene (PS) fibrous mats are quite limited. The introduction of various concentrations of poly (butylacrylate) adhesives (PBAs) into PS solutions led to the fabrication of point-bonded electrospun PS fibrous mats with good mechanical strength. The morphologies of PS/PBA fibers with varying PBA content (0-50 wt%) were investigated using scanning electron microscopy (SEM), and the results were compared with pure PS and PBA fibers fabricated with various solvents. SEM images indicated that point-bonded PS/PBA fibers were uniformly distributed with an average diameter of 1-2 µm. On increasing concentration of PBA up to 20 wt%, porous PS/PBA fibrous mats were obtained. However, solid films were formed at very high concentrations of PBA. The Young's modulus and tensile strength of PS/ PBA fibrous mats increased up to 52.4 and 2.7 MPa, respectively. The resultant enhancement of the mechanical properties of PS fibrous mats on addition of PBA increases the number of potential applications of these materials. POLYM. ENG. SCI., 51:894-901, 2011. [C]2011 Society of Plastics Engineers, INTRODUCTION Electrospinning is a process for generating electrostatic nanofibers that uses electrical forces to produce polymers or composite fibrous mats with diameters on the micrometer to nanometer scale (1-3). This [...]

Introduction: Grading of hydronephrosis severity on postnatal renal ultrasound guides management decisions in antenatal hydronephrosis (ANH). Multiple systems exist to help standardize hydronephrosis grading, yet poor inter-observer reliability persists. Machine learning methods may provide tools to improve the efficiency and accuracy of hydronephrosis grading., Objective: To develop an automated convolutional neural network (CNN) model to classify hydronephrosis on renal ultrasound imaging according to the Society of Fetal Urology (SFU) system as potential clinical adjunct., Study Design: A cross-sectional, single-institution cohort of postnatal renal ultrasounds with radiologist SFU grading from pediatric patients with and without hydronephrosis of stable severity was obtained. Imaging labels were used to automatedly select sagittal and transverse grey-scale renal images from all available studies from each patient. A VGG16 pre-trained ImageNet CNN model analyzed these preprocessed images. Three-fold stratified cross-validation was used to build and evaluate the model that was used to classify renal ultrasounds on a per patient basis into five classes based on the SFU system (normal, SFU I, SFU II, SFU III, or SFU IV). These predictions were compared to radiologist grading. Confusion matrices evaluated model performance. Gradient class activation mapping demonstrated imaging features driving model predictions., Results: We identified 710 patients with 4659 postnatal renal ultrasound series. Per radiologist grading, 183 were normal, 157 were SFU I, 132 were SFU II, 100 were SFU III, and 138 were SFU IV. The machine learning model predicted hydronephrosis grade with 82.0% (95% CI: 75-83%) overall accuracy and classified 97.6% (95% CI: 95-98%) of the patients correctly or within one grade of the radiologist grade. The model classified 92.3% (95% CI: 86-95%) normal, 73.2% (95% CI: 69-76%) SFU I, 73.5% (95% CI: 67-75%) SFU II, 79.0% (95% CI: 73-82%) SFU III, and 88.4% (95% CI: 85-92%) SFU IV patients accurately. Gradient class activation mapping demonstrated that the ultrasound appearance of the renal collecting system drove the model's predictions., Discussion: The CNN-based model classified hydronephrosis on renal ultrasounds automatically and accurately based on the expected imaging features in the SFU system. Compared to prior studies, the model functioned more automatically with greater accuracy. Limitations include the retrospective, relatively small cohort, and averaging across multiple imaging studies per patient., Conclusions: An automated CNN-based system classified hydronephrosis on renal ultrasounds according to the SFU system with promising accuracy based on appropriate imaging features. These findings suggest a possible adjunctive role for machine learning systems in the grading of ANH., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To project the number and proportion of women in the urology workforce using recent demographic trends and develop an app to explore updated projections using future data., Methods: Demographic data were obtained from AUA Censuses and ACGME Data Resource Books. The proportion of female graduating urology residents was characterized with a logistic growth model. "Stock and Flow" models were used to project future population numbers and proportions of female practicing urologists, accounting for trainee demographics, retirement trends, and growth in the field., Results: Assuming growth in urology graduate numbers and continued logistic growth in the proportion of women, 10,957 practicing urologists (38%) will be female by 2062. If the rate of women entering urology residency stagnates, 7038 urologists (24%) will be female. If the retirement rates for women in urology change to mirror those of men and the proportion of female residents continues to experience logistic growth, 11,178 urologists (38%) will be female. An interactive app was designed to allow for a range of assumptions and future data: https://stephenrho.shinyapps.io/uro-workforce/., Conclusion: Workforce projections should incorporate recent growth in numbers of female residents. If current growth continues, 38% of urologists will be female by 2062. The app allows for exploration of different scenarios and can be updated with new data. The projections demonstrate the need for targeted efforts to recruit women into urology, address disparities within the field, and work toward retaining female urologists. We must continue working toward an equitable future workforce that can address the impending shortage of urologists., Competing Interests: DECLARATION OF COMPETING INTEREST None Declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: While microbiome and host regulation contribute independently to many disease states, it is unclear how circumcision in pediatric population influences subsequent changes in penile microbiome., Objective: Our study aims to analyze jointly paired taxonomic profiles and assess pathways implicated in inflammation, barrier protection, and energy metabolism., Design, Setting, and Participants: We analyzed 11 paired samples, periurethral collection, before and after circumcision, to generate microbiome and mycobiome profiling. Sample preparation of 16S ribosomal RNA and internal transcribed spacer sequencing was adapted from the methods developed by the National Institutes of Health Human Microbiome Project., Outcome Measurements and Statistical Analysis: We obtained the predictive functional attributes of the microbial communities between samples using Silva-Tax4Fun and the Greengenes-Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) approach. The predictive functioning of the microbial communities was determined by linearly combining the normalized taxonomic abundances into the precomputed association matrix of Kyoto Encyclopedia of Genes and Genomes orthology reference profiles., Results and Limitations: Several notable microbiome and mycobiome compositional differences were observed between pre- and postcircumcision patients. Pairwise comparisons across taxa revealed a significant decrease (p < 0.05, false discovery rate corrected) of microbiome organisms (Clostridiales, Bacteroidales, and Campylobacterales) and mycobiome (Saccharomycetales and Pleosporales) following circumcision. A total of 14 pathways were found to differ in abundance between the pre- and postcircumcision groups (p < 0.005, false discovery rate <0.1 and linear discriminant analysis score >3; five enriched and nine depleted). The pathways reduced after circumcision were mostly involved with amino acid and glucose metabolism, while pathways prior to circumcision were enriched in genetic information processing and transcription processes. As expected, enrichment in methyl-accepting chemotaxis protein, an integral membrane protein involved in directed motility of microbes to chemical cues and environment, occurred prior to circumcision, while the filamentous hemagglutinin pathway (a strong immunogenic protein) was depleted after circumcision CONCLUSIONS: Our results offer greater insight into the host-microbiota relationship of penile circumcision and may serve to lay the groundwork for future studies focused on drivers of inflammation, infection, and oncogenesis., Patient Summary: Our study showed a significant reduction in bacteria and fungi after circumcision, particularly anaerobic bacteria, which are known to be potential inducers of inflammation and cancer. This is the first study of its kind showing the changes in microbiome after circumcision, and some of the changes that occur in healthy infants after circumcision that may explain the differences in cancer and inflammatory disorders in adulthood., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Reports of adult orchidopexy for bilateral undescended testicles (bUDT) are sparse, and fertility outcomes are not well established. Our aim was to determine prognosis for restoration of spermatogenesis among adult men (≥18 years) undergoing orchidopexy for bUDT., Methods: A systematic literature review, conforming to the PRISMA statement, was conducted using the PubMed/MEDLINE and EMBASE databases through March 2020 using search terms "adult" AND "bilateral orchidopexy" OR "bilateral cryptorchidism." Relevant referenced articles from non-indexed journal were identified by Google Scholar search and additionally included., Results: Fifty-seven publications including adult men with uncorrected bilateral UDTs were identified. Baseline semen analysis was reported in 157 men, all of whom demonstrated azoospermia. Testosterone values were reported in 82 cases and were normal in 89%. Germ cells could not be identified in 72.6% of histologic specimens from 62 testicles. Abdominal testicles more frequently lacked germ cells (90%, p = 0.038) on univariate analysis. Eleven cases identified ejaculated spermatozoa following adult bilateral orchidopexy (8 publications). Sperm extraction (TESE) during orchidopexy or orchiectomy was reported in 13 men without success. Delayed TESE (median 10 months) was performed in 22 persistently azoospermic men with success in 10 (45.5%), none of whom had abdominal testicles prior to orchidopexy. Six men experienced successful paternity via natural conception (3) or assisted reproduction (3)., Conclusion: Fertility is possible in adult men with inguinal bUDT following orchidopexy. Subsequent sperm retrieval may involve ejaculated specimens or delayed TESE. TESE performed prior to or at time of orchidopexy is unlikely to be of benefit., (© 2020 American Society of Andrology and European Academy of Andrology.)

While radical orchiectomy remains the gold standard for testicular cancer, partial orchiectomy has become a well-accepted organ-sparing approach for benign testicular tumors in pre-pubertal patients. The aims of testicular-sparing surgery include prevention of over-treatment, preservation of future hormonal and reproductive function, and provision of a durable cure. For pre-pubertal patients, who have a high likelihood of benign lesions, partial orchiectomy provides effective treatment, owing to the high reliability of scrotal ultrasound (US) and intraoperative frozen section. In adolescent and young adult patients, who are more likely to harbor malignant pathology, the role of partial orchiectomy is less clear. Testis-sparing surgery is being reported with greater frequency in the adult literature for small testicular masses and for situations in which radical orchiectomy would result in an anorchia. More recently, a testis-sparing approach has also been described for carefully-selected post-pubertal pediatric patients. This review will highlight the role of partial orchiectomy in pediatric patients (<18 years old)., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-19-815). The series “Pediatric Urologic Malignancies” was commissioned by the editorial office without any funding or sponsorship. The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

This study quantified the monetary cost of family caregiving for 51 patients with different severity of dementia. The mean annual informal cost of care was higher (M=SG$44,530.55, SD=SG$31,354.82) compared to the mean annual formal cost of care (M=SG$25,654.11, SD=SG$10,016.48). Costs were found to increase with severity of dementia (Severe: SG$47,251.30; Moderate: SG$38,607.84; Mild: SG$13,847.68). For each point increase in CMMSE scores, the informal cost lowered by SG$1,173.94. There was a significant negative correlation of cost and cognitive impairment but not functional impairment. The informal cost of care did not vary much with or without the use of day care centres, however the costs for those who did not have domestic helpers (DHs) was more than twice the costs for those with DHs. Results from this study show there were cost savings in care of people with dementia with DHs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Organ-sparing approaches have been applied to the treatment of a variety of urologic tumors in both the realms of adult and pediatric urology, with the goals of minimizing overtreatment of benign lesions, preserving function, and providing durable cure. The predominance of benign tumors in prepubertal patients and the reliability of both ultrasound and intraoperative frozen sections have resulted in a marked shift toward testis-sparing approaches over the last few decades. The role of testis sparing in the adolescent population is presently unclear, although there have been increasing reports of successful organ-sparing surgery for testis tumors in the adult literature. This review presents recent trends in testis-sparing approaches for both pediatric and adolescent patients, the operative technique, and some of the controversies related to testis-sparing surgery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Platelet activation and subsequent protein release play an important role in healthy hemostasis and inflammatory responses, yet the identity and quantity of proteins in the platelet releasate are still debated. Here, we present a reversed releasate proteomics approach to determine unambiguously and quantitatively proteins released from activated platelets., Approach and Results: Isolated platelets were mock and fully stimulated after which the released proteins in the supernatant were removed. Using high-end proteomics technology (2D chromatography, stable isotope labeling, electron transfer dissociation, and high collision dissociation fragmentation) allowed us to quantitatively discriminate the released proteins from uncontrolled lysis products. Monitoring the copy numbers of ≈ 4500 platelet proteins, we observed that after stimulation via thrombin and collagen, only 124 (<3%) proteins were significantly released (P<0.05). The released proteins span a concentration range of ≥ 5 orders, as confirmed by ELISA. The released proteins were highly enriched in secretion tags and contained all known factors at high concentrations (>100 ng/mL, eg, thrombospondin, von Willebrand factor, and platelet factor 4). Interestingly, in the lower concentration range of the releasate many novel factors were identified., Conclusions: Our reversed releasate dataset forms the first unambiguous, in depth repository for molecular factors released by platelets.

Purpose: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention., Materials and Methods: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons., Results: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression., Conclusions: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aflatoxin B(1) (AFB(1) ) is a potent mutagen and an important risk factor for hepatocellular carcinoma (HCC) in humans. Transgenic mouse strains and cells in culture have been used to detect different types of mutations caused by AFB(1) and investigate the molecular determinants of their location and frequency. The AFB(1) mutational spectrum in the gpt gene was markedly different in AS52 cells compared with the liver in gpt delta B6C3F1 transgenic mice. The results demonstrate the importance of metabolism, chromosomal location, transcription and selection conditions on mutational spectra., (Copyright © 2012 Wiley Periodicals, Inc.)

Aflatoxin B (1) (AFB(1)) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB(1)-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks, the spectrum at a second locus, the red/gam genes of the mouse λEG10 transgene. Whereas the gpt locus is typically used to define local base changes, the red/gam genes, via the Spi(-) assay, often are used to detect more global mutations such as large deletions and rearrangements. Three weeks after dosing with AFB(1), there was a 10-fold increase over the control in the Spi(-) mutant fraction (MF) in liver DNA; after 10 weeks, a further increase was observed. The MF in the gpt gene was also increased at 10 weeks compared with the MF at 3 weeks. No gender-specific differences were found in the Spi(-) or gpt MFs. Whereas Spi(-) mutations often signal large genetic changes, they did not in this specific case. The Spi(-) spectrum was dominated by GC to TA transversions, with one exceptionally strong hotspot at position 314. Using two genetic loci, the data show a strong preference for the induction of GC to TA mutations in mice, which is the dominant mutation seen in people exposed to aflatoxin.

Exposure to genotoxic chemicals at a young age increases cancer incidence later in life. Aflatoxin B(1) (AFB(1)) is a potent genotoxin that induces hepatocellular carcinoma (HCC) in many animal species and in humans. Whereas adult mice are insensitive to aflatoxin-induced carcinogenesis, mice treated with AFB(1) shortly after birth develop a high incidence of HCC in adulthood. Furthermore, the incidence of HCC in adult male mice treated as infants is much greater than in females, reasons for which are unclear. In this study, treatment with AFB(1) produced similar levels of DNA damage and mutations in the liver of newborn male and female gpt delta B6C3F1 mice. Twenty-four hours after dosing with AFB(1) (6 mg/kg), the highly mutagenic AFB(1)-FAPY adduct was present at twice the level of AFB(1)-N(7)-guanine in liver DNA of males and females. A multiple dose regimen (3 × 2 mg/kg), while delivering the same total dose, resulted in lower AFB(1) adduct levels. Mutation frequencies in the gpt transgene in liver were increased by 20- to 30-fold. The most prominent mutations in AFB(1)-treated mice were G:C to T:A transversions and G:C to A:T transitions. At this 21-day time point, no significant differences were found in mutation frequency or types of mutations between males and females. These results show that infant male and female B6C3F1 mice experience similar amounts of DNA damage and mutation from AFB(1) that may initiate the neoplastic process. The gender difference in the subsequent development of HCC highlights the importance of elucidating additional factors that modulate HCC development.

Purpose: Mesenchymal stem cells have various therapeutic benefits in various organ injury models. Bladder outlet obstruction causes smooth muscle hypertrophy and fibrosis, leading to lowered compliance, increased storage pressures and renal injury. Decreased blood flow and hypoxia may contribute to obstruction related bladder decompensation. We used a mouse model to determine whether mesenchymal stem cell recruitment occurred after bladder outlet obstruction and whether this was associated with changes in bladder hypoxia, histology and function. We also identified potential chemokines involved in mesenchymal stem cell recruitment., Materials and Methods: A total of 20 female mice underwent bladder outlet obstruction. Three days later 2 million green fluorescent protein labeled mesenchymal stem cells were intravenously administered. After 4 weeks urodynamic and histological evaluation was performed. Quantitative reverse transcriptase-polymerase chain reaction was done to determine relative expression of the chemokines CCL2, CCL20, CCL25, CXCL9 and CXCL16. We simultaneously studied mice with bladder outlet obstruction only without mesenchymal stem cell injection and a control group., Results: In 10 of 15 surviving mesenchymal stem cell injected mice mesenchymal stem cells were identified in the detrusor, and decreased hypoxia, hypertrophy and fibrosis was seen. Nine of 10 mice with mesenchymal stem cell engraftment had improved compliance compared to those without engraftment (mean±SD 9.6±5.1 vs 3.9±2.6 μl/cm H2O, p=0.012). Polymerase chain reaction revealed a 2-fold increase in CCL2 expression but there were no significant changes in other chemokine levels., Conclusions: Mesenchymal stem cell recruitment to the bladder after bladder outlet obstruction appears to be associated with increased blood flow and decreased tissue hypoxia, which may contribute to improvement in histopathological and functional parameters. Mesenchymal stem cell recruitment may be related to CCL2 over expression. Additional studies in larger samples are needed but these initial results suggest a potential role for mesenchymal stem cell based therapy for bladder outlet obstruction related bladder injury., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To provide a comprehensive overview of the clinical features, diagnosis, current management strategies, and outcomes of cloacal exstrophy., Methods: A PUBMED/Medline search of the literature was performed on cloacal exstrophy focusing on associated anomalies, treatment, and quality of life issues., Results: The incidence of cloacal exstrophy is between 1 in 200,000 and 400,000 live births. Survival rates now approach 100% secondary to improved understanding of underlying abnormalities and advances in neonatal care and surgical technique. Important principles of initial management include proper nutritional support, early closure of exstrophy, and preservation of intestinal length. The achievement of urinary and fecal continence remains a challenge. Data for long-term outcomes are now emerging which provide new insight into issues of gender identity, function, and psychosocial development of these patients., Conclusion: Cloacal exstrophy remains a rare and complex congenital anomaly, characterized by an array of anatomical defects affecting multiple organ systems. A multidisciplinary approach to management is advocated with a focus on optimization of patient function and quality of life., (Copyright © 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

The gene mutated in Bloom's syndrome, BLM, is important in the repair of damaged replication forks, and it has both pro- and anti-recombinogenic roles in homologous recombination (HR). At damaged forks, BLM interacts with RAD51 recombinase, the essential enzyme in HR that catalyzes homology-dependent strand invasion. We have previously shown that defects in BLM modification by the small ubiquitin-related modifier (SUMO) cause increased gamma-H2AX foci. Because the increased gamma-H2AX could result from defective repair of spontaneous DNA damage, we hypothesized that SUMO modification regulates BLM's function in HR repair at damaged forks. To test this hypothesis, we treated cells that stably expressed a normal BLM (BLM+) or a SUMO-mutant BLM (SM-BLM) with hydroxyurea (HU) and examined the effects of stalled replication forks on RAD51 and its DNA repair functions. HU treatment generated excess gamma-H2AX in SM-BLM compared to BLM+ cells, consistent with a defect in replication-fork repair. SM-BLM cells accumulated increased numbers of DNA breaks and were hypersensitive to DNA damage. Importantly, HU treatment failed to induce sister-chromatid exchanges in SM-BLM cells compared to BLM+ cells, indicating a specific defect in HR repair and suggesting that RAD51 function could be compromised. Consistent with this hypothesis, RAD51 localization to HU-induced repair foci was impaired in SM-BLM cells. These data suggested that RAD51 might interact noncovalently with SUMO. We found that in vitro RAD51 interacts noncovalently with SUMO and that it interacts more efficiently with SUMO-modified BLM compared to unmodified BLM. These data suggest that SUMOylation controls the switch between BLM's pro- and anti-recombinogenic roles in HR. In the absence of BLM SUMOylation, BLM perturbs RAD51 localization at damaged replication forks and inhibits fork repair by HR. Conversely, BLM SUMOylation relieves its inhibitory effects on HR, and it promotes RAD51 function., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Several algorithms exist for the management of prenatally diagnosed hydronephrosis due to ureteropelvic junction obstruction (UPJO). We utilize a conservative and practical approach emphasizing observation, with less frequent use of renal flow scans (RFS). We reviewed the results of 143 pediatric patients with congenital UPJO managed at our institution, focusing on surveillance and selective utilization of RFS, according to a standardized protocol., Materials and Methods: Charts of all infants with prenatally detected UPJO treated surgically or followed conservatively according to our protocol were reviewed. Patients were initially evaluated with ultrasound (US), voiding cystourethrogram, and RFS. Successive follow-up was with interval US. RFS was reserved for those with worsening hydronephrosis or that which failed to improve on US by 1 year. Radiographic studies and operative reports were examined. Gender, side of UPJO, degree of hydronephrosis, mode of management, and current status of the patients were noted., Results: The records of 143 patients and a total of 198 renal units (RU) were reviewed. The male:female ratio was 2.7. UPJO was unilateral in 88 (61%) patients and occurred more frequently on the left side (68%). Obstruction was bilateral in 55 (39%) patients. Initial US grade of hydronephrosis was Grade 1 in 56 RU (28%), Grade 2 in 51 RU (26%), Grade 3 in 50 RU (25%) and Grade 4 in 41 RU (21%). 178 RU (90%) were followed conservatively, while open dismembered pyeloplasty was the initial therapeutic approach in 20 RU (10%). The mean age at the time of surgery was 15.95+/-14.60 weeks (range 2-60). Indications included low differential renal function (DRF) (n=12), absence of tracer clearance from the renal pelvis (n=2), parental preference (n=3), and acute renal failure (n=3). Postoperative course was uneventful during 33.43+/-33.53 months (range 2-120) with favorable US and RFS results. In conservatively managed patients, mean follow-up time was 14.94+/-14.35 months (range 1.5-142). Spontaneous resolution of hydronephrosis was observed in 87 RU (49%), while 10 RU (5.6%) eventually required surgery for worsening appearance or function on US or RFS, respectively (n=8), symptom development (n=3), and/or parental preference due to persistently prolonged T1/2 (n=4). Seventy-two RU (40.4%) remain under surveillance with improvement (47.2%) or stable hydronephrosis (47.2%) in 94.4%. Decreased DRF occurred in 1 RU. Nine RU (5%) were lost to follow-up. With application of this algorithm, only 12% of patients underwent two or more RFS., Conclusion: Pyeloplasty may be performed safely in infants when indicated; however, the majority of children with UPJO can be managed conservatively. Spontaneous resolution of hydronephrosis and/or favorable prognosis was encountered in 87% of conservatively managed RU. The use of a standard US grading system, selective utilization of follow-up renal function testing, and parental compliance are important factors in successful management.

Aims: Vaginal distension (VD) in outbred rats has been shown to decrease urethral resistance, as well as increase the expression of the stem cell-homing chemokine, monocyte chemotactic factor 3 (MCP-3), but not stromal derived factor 1 (SDF-1). The aim of this study was to determine if similar responses are induced by VD in an inbred rat strain., Methods: Forty female Lewis rats underwent VD or sham VD followed by leak point pressure (LPP) testing 4 or 10 days later. Ten additional rats served as controls. The urethra and vagina were then dissected for histology. To examine chemokine expression, eight additional rats underwent VD with organs harvested immediately or 1 day after the procedure for reverse transcriptase polymerase chain reaction (RT-PCR) of MCP-3 and SDF-1. Four age-matched rats served as controls., Results: Four days after VD, LPP was significantly lower in VD rats (14.3 +/- 1.6 cm H(2)O) than controls (18.7 +/- 1.3 cm H(2)O). Ten days after VD, LPP in both VD (19.7 +/- 2.6 cm H(2)O) and sham (18.4 +/- 1.3 cm H(2)O) groups was not significantly different from controls. Urethral histology demonstrated marked disruption and atrophy of smooth and striated muscle in VD rats compared to shams and controls. RT-PCR yielded a 25-fold significant increase in expression of urethral MCP-3 immediately following VD. SDF-1 was significantly decreased in the urethra and vagina immediately after VD and in the bladder 24 hr after VD., Conclusion: VD in Lewis rats produces functional, histological and molecular results similar to that of outbred rats. This model could be utilized in future studies investigating cellular transplant methods of improving urethral function., ((c) 2008 Wiley-Liss, Inc.)

Homologous recombination (HR) is a genetic mechanism in somatic cells that repairs DNA double-strand breaks and restores productive DNA synthesis following disruption of replication forks. Although HR is indispensable for maintaining genome integrity, it must be tightly regulated to avoid harmful outcomes. HR-associated genomic instabilities arise in three human genetic disorders, Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), which are caused by defects in three individual proteins of the RecQ family of helicases, BLM, WRN, and RECQL4, respectively. Cells derived from persons with these syndromes display varying types of genomic instability as evidenced by the presence of different kinds of chromosomal abnormalities and different sensitivities to DNA damaging agents. Persons with these syndromes exhibit a variety of developmental defects and are predisposed to a wide range of cancers. WS and RTS are further characterized by premature aging. Recent research has shown many connections between all three proteins and the regulation of excess HR. Here, we illustrate the elaborate networks of BLM, WRN, and RECQL4 in regulating HR, and the potential mechanistic linkages to cancer and aging.

Urologic congenital anomalies associated with ureteropelvic obstruction (UPJO) have been previously characterized; however, less data are available regarding these associations in a prenatally diagnosed population. A retrospective study was conducted to evaluate significant clinical features and urological anomalies associated with prenatally diagnosed UPJO. The records of 143 children with prenatally diagnosed hydronephrosis secondary to UPJO were retrospectively reviewed. The gender, side of obstruction, degree of hydronephrosis, associated clinical features, and urological anomalies were noted. Hundred and forty-three children (M/F = 2.7) with a total of 198 affected renal units (RU) presenting with unilateral (61%) or bilateral (39%) UPJO were enrolled. In cases of unilateral obstruction, the left side was affected in 60 children (68%). The grade of hydronephrosis was Grade 1 in 56 RU (28%), Grade 2 in 51 RU (26%), Grade 3 in 50 RU (25%) and Grade 4 in 41 RU (21%). Associated clinical features included prematurity (n = 7, 4.9%), twinning (n = 5, 3.5%) and presentation with renal failure (RF) (n = 2). Excluding contralateral UPJO, other urologic anomalies were encountered in 29 patients (20.3%). Associated vesicoureteral reflux (VUR) was encountered in 11 patients (7.7%, M/F = 2.7). Pyeloplasty was required more often in children with associated VUR (54.5 vs. 18.2%) (P = 0.01). Contralateral multicystic dysplastic kidney (MCDK) was encountered in six patients (M/F = 2), one of whom presented with RF. One child carried the diagnosis of Schinzel-Giedion syndrome (SGS), demonstrating severe developmental and neurological disorders and bilateral hydronephrosis. The more frequent occurrence of UPJO in males with predominantly left-sided location, association with VUR and MCDK, and increased frequency of bilaterality in our prenatally diagnosed patients were similar to historical reports. In addition, prematurity and twinning were independently associated with UPJO. The higher rate of pyeloplasty in patients with associated reflux warrants further investigation.

Purpose: Vaginal delivery is a risk factor for stress urinary incontinence. Rat models of simulated childbirth demonstrated hypoxia of the urogenital organs as well as the development of stress urinary incontinence following vaginal distention. Stromal derived factor-1 and monocyte chemotactic protein-3 were identified as cytokines that are over expressed after myocardial ischemia and signal stem cell migration to ischemic sites in a rat cardiac model. Given the focal hypoxia observed with vaginal distention, we characterized stromal derived factor-1 and monocyte chemotactic protein-3 expression by pelvic organ tissues after vaginal distention., Materials and Methods: A total of 16 female rats were randomized into 4 groups. Two groups underwent vaginal distention with harvest of pelvic tissues immediately or 24 hours after vaginal distention, a sham group underwent anesthesia only and a control group underwent no intervention. Reverse transcriptase-polymerase chain reaction was performed on RNA extracted from the urogenital organs., Results: Monocyte chemotactic protein-3 expression in the urethra was increased 20 and 6-fold immediately and 24 hours after vaginal distention, respectively. Monocyte chemotactic protein-3 was 8 and 4-fold increased in the vagina after vaginal distention. There was no difference in monocyte chemotactic protein-3 expression in the rectum or bladder in any group. Stromal derived factor-1 was significantly under expressed immediately after vaginal distention in all tissues., Conclusions: Monocyte chemotactic protein-3 is significantly over expressed in rat urethral and vaginal tissues immediately following vaginal distention with above normal but decreasing expression 24 hours later. The association between monocyte chemotactic protein-3 over expression and targeted stem cell migration is under investigation. Successful characterization and control of such a repair mechanism in the lower urinary tract would introduce the potential for novel nonoperative treatments and/or preventive measures for stress urinary incontinence.

The RecQ family of DNA helicases consists of specialized DNA unwinding enzymes that promote genomic stability through their participation in a number of cellular processes, including DNA replication, recombination, DNA damage signaling, and DNA repair pathways. Mutations resulting in the inactivation of some but not all members of the RecQ helicase family can lead to human syndromes which are characterized by marked chromosomal instability and an increased predisposition to cancer. An evolutionarily conserved interaction between RecQ helicases and topoisomerase 3s has been established, and this interaction is important in the regulation of recombination and genomic stability. Topoisomerases are critical in the cell because they relieve helical stress that arises when DNA is unwound. Topoisomerases function by breaking and rejoining DNA. By inhibition of the rejoining function, topoisomerase inhibitors are potent chemotherapeutic agents that have been used successfully in the treatment of hematologic malignancies and other cancers. This review discusses the roles of RecQ helicases in genomic stability, the interplay between RecQ helicases and topoisomerase 3s, and current and future prospects for targeting these interactions to develop novel anticancer therapies.

Mutations in the RECQL4 helicase gene have been linked to Rothmund-Thomson syndrome (RTS), which is characterized by poikiloderma, growth deficiency, and a predisposition to cancer. Examination of RECQL4 subcellular localization in live cells demonstrated a nucleoplasmic pattern and, to a lesser degree, staining in nucleoli. Analysis of RECQL4-GFP deletion mutants revealed two nuclear localization regions in the N-terminal region of RECQL4 and a nucleolar localization signal at amino acids 376-386. RECQL4 localization did not change after treatment with the DNA-damaging agents bleomycin, etoposide, UV irradiation and gamma irradiation, in contrast to the Bloom and Werner syndrome helicases that relocate to distinct nuclear foci after damage. However, in a significant number of cells exposed to hydrogen peroxide or streptonigrin, RECQL4 accumulated in nucleoli. Using a T7 phage display screen, we determined that RECQL4 interacts with poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme that promotes genomic integrity through its involvement in DNA repair and signaling pathways. The RECQL4 nucleolar localization was inhibited by pretreatment with a PARP-1 inhibitor. The C-terminal portion of RECQL4 was found to be an in vitro substrate for PARP-1. These results demonstrate changes in the intracellular localization of RECQL4 in response to oxidative stress and identify an interaction between RECQL4 and PARP-1.

Purpose: Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model., Experimental Design: MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly., Results: STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity., Conclusions: This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

Giant cell fibroblastoma (GCF) is an uncommon fibroblastic tumor of childhood. Appearing as superficial, poorly circumscribed masses, they are characterized histologically by a mixture of cellular and angiectoid areas with empty cleft-like spaces, lined by spindle-shaped and multinucleated giant cells. We present a case of an 11-month-old boy with penile GCF treated with local excision. The patient presented with a recurrent penile mass 1 year later and underwent repeat excision. Pathologic examination confirmed recurrent GCF. GCF is a benign, but locally recurrent tumor, as demonstrated by our case. To our knowledge, no cases of penile involvement have been previously reported.

We describe the docking of selected steroidal and non-steroidal estrone sulphatase inhibitors, including the Phase I clinical trial candidate 667COUMATE (6), into the active site of human carbonic anhydrase II (hCA II). The docking scores are compared with the inhibition of hCA II and show good correlation with biological activity.

Background: There is now abundant evidence that inhibition of steroid sulphatase alone or in conjunction with inhibition of aromatase may enhance the response of postmenopausal patients with hormone-dependent breast cancer to this type of endocrine therapy. Additionally, sulphatase inhibition has been proposed to be of potential therapeutic benefit in the immune system and for neuro-degenerative diseases. After the finding that our first highly potent active site-directed steroid sulphatase inhibitor, oestrone-3-O-sulphamate (EMATE), was highly oestrogenic, we proposed non-steroidal coumarin sulphamates such as 4-methylcoumarin-7-O-sulphamate (COUMATE) as alternative non-steroidal steroid sulphatase inhibitors. In this work, we describe how tricyclic coumarin-based sulphamates have been developed which are even more potent than COUMATE, are non-oestrogenic and orally active. We also discuss potential mechanisms of action., Results: 4-Ethyl- (4), 4-(n-propyl)- (6), 3-ethyl-4-methyl- (8), 4-methyl-3-(n-propyl)coumarin-7-O-sulphamate (11); the tricyclic derivatives 665COUMATE (13), 666COUMATE (15), 667COUMATE (17), 668COUMATE (20) and the tricyclic oxepin sulphamate (22) were synthesised. In a placental microsome preparation, all of these analogues were found to be more active than COUMATE in the inhibition of oestrone sulphatase, with the most potent inhibitor being 667COUMATE which has an IC(50) of 8 nM, some 3-fold lower than that for EMATE (25 nM). In addition, 667COUMATE was also found to inhibit DHEA-sulphatase some 25-fold more potently than EMATE in a placental microsome preparation. Like EMATE, 667COUMATE acts in a time- and concentration-dependent manner, suggesting that it is an active site-directed inhibitor. However, in contrast to EMATE, 667COUMATE has the important advantage of not being oestrogenic. In addition, we propose several diverse mechanisms of action for this active site-directed steroid sulphatase inhibitor in the light of recent publications on the crystal structures of human arylsulphatases A and B and the catalytic site topology for the hydrolysis of a sulphate ester., Conclusions: A highly potent non-steroidal, non-oestrogenic and irreversible steroid sulphatase inhibitor has been developed. Several mechanisms of action for an active site-directed steroid sulphatase inhibitor are proposed. With 667COUMATE now in pre-clinical development for clinical trial, this should allow the biological and/or clinical significance of steroid sulphatase inhibitors in the treatment of postmenopausal women with hormone-dependent breast cancer and other therapeutic indications to be fully evaluated.