Comparison of urology residency training between the United States and China.

OBJECTIVE: This study compares the present status and traits of urology residency programs in the United States and China. METHODS: The flow path, structure, curriculum, operative experience, scholarly activities, evaluation systems and other aspects of training were comparatively evaluated between China and the United States. RESULTS: Urology residency training programs are different between China and the United States in many aspects. Admission requirements for the United States urology residency program are more rigorous, and the specialty training program in the United States is more concentrated. Furthermore, residency programs in USA have much more practical clinical and research training, and their evaluation process is more diverse, and it has been designed to assess competencies. Moreover, job opportunities after residency substantially differ between these two countries. Becoming an independent urologic surgeon is not the specific goal of the Urology residency training program in China, and it would require more training time than in the United States. CONCLUSION: Urology residency training programs in the United States and China have a unique format and characteristics. The training programs in China are focused on general techniques and procedures, while training programs in USA follow a more standardized curriculum. Both USA and China may complement each other to create training programs that would ultimately provide high-quality patient care.

Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo.

Arterial conduits are increasingly preferred for surgical bypass because of inherent functional properties conferred by arterial endothelial cells, especially nitric oxide production in response to physiologic stimuli. Here we tested whether endothelial progenitor cells (EPCs) can replace arterial endothelial cells and promote patency in tissue-engineered small-diameter blood vessels (4 mm). We isolated EPCs from peripheral blood of sheep, expanded them ex vivo and then seeded them on decellularized porcine iliac vessels. EPC-seeded grafts remained patent for 130 days as a carotid interposition graft in sheep, whereas non-seeded grafts occluded within 15 days. The EPC-explanted grafts exhibited contractile activity and nitric-oxide-mediated vascular relaxation that were similar to native carotid arteries. These results indicate that EPCs can function similarly to arterial endothelial cells and thereby confer longer vascular-graft survival. Due to their unique properties, EPCs might have other general applications for tissue-engineered structures and in treating vascular diseases.

Basic science research in urology training.

The role of basic science exposure during urology training is a timely topic that is relevant to urologic health and to the training of new physician scientists. Today, researchers are needed for the advancement of this specialty, and involvement in basic research will foster understanding of basic scientific concepts and the development of critical thinking skills, which will, in turn, improve clinical performance. If research education is not included in urology training, future urologists may not be as likely to contribute to scientific discoveries.Currently, only a minority of urologists in training are currently exposed to significant research experience. In addition, the number of physician-scientists in urology has been decreasing over the last two decades, as fewer physicians are willing to undertake a career in academics and perform basic research. However, to ensure that the field of urology is driving forward and bringing novel techniques to patients, it is clear that more research-trained urologists are needed. In this article we will analyse the current status of basic research in urology training and discuss the importance of and obstacles to successful addition of research into the medical training curricula. Further, we will highlight different opportunities for trainees to obtain significant research exposure in urology.

Human Cortex Spheroid with a Functional Blood Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling.

The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex. To date, most in vitro BBB models utilize endothelial cells, pericytes and astrocytes. We report a 3D spheroid model of the BBB comprising all major cell types, including neurons, microglia and oligodendrocytes, to recapitulate more closely normal human brain tissue. Spheroids show expression of tight junctions, adherens junctions, adherens junction-associated proteins and cell specific markers. Functional assessment using MPTP, MPP+ and mercury chloride indicate charge selectivity through the barrier. Junctional protein distribution was altered under hypoxic conditions. Our spheroid model may have potential applications in drug discovery, disease modeling, neurotoxicity and cytotoxicity testing.

Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder.

The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified. Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth. This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo. ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder. These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury. Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder. Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.

Tunica repair with acellular bladder matrix maintains corporal tissue function.

Penile conditions, such as Peyronie's disease or tumor resection may require surgical reconstruction of the tunica albuginea. Various materials have been proposed, as a biomaterial for tunica albuginea repair, however, little functional data are available. We examined the applicability and functional outcome of a collagen-based matrix derived from the bladder (acellular bladder matrix (ABM)), as a biomaterial for tunica repair. Biocompatibility testing was performed on the matrix, which included mitochondrial metabolic activity, cell viability and apoptosis. Approximately 50% of the dorsal penile tunica albuginea was replaced with the collagen-based matrix patch after surgical removal in 24 New Zealand White rabbits. Cavernosometry and cavernosography were performed. The animals were killed 1, 2 and 3 months after surgery for analyses. The matrix showed excellent biocompatibility. All animals implanted with the matrix survived without any noticeable untoward effects. There was no evidence of inflammation or infection at the time of retrieval. Cavernosometry of the implanted animals demonstrated normal intracavernosal pressures with visual erections. Cavernosography of the repaired corpora showed a normal anatomical configuration. Biomechanical analysis of the retrieved matrices demonstrated similar tensile strengths as native tunica. Histologically, there was only a minimal inflammatory response, which gradually decreased over time. These results show that ABM is biocompatible, durable and effective when used as a tunica substitute. The matrix may be useful as an off-the-shelf biomaterial for patients requiring tunica albuginea repair.

De novo reconstitution of a functional mammalian urinary bladder by tissue engineering.

Human organ replacement is limited by a donor shortage, problems with tissue compatibility, and rejection. Creation of an organ with autologous tissue would be advantageous. In this study, transplantable urinary bladder neo-organs were reproducibly created in vitro from urothelial and smooth muscle cells grown in culture from canine native bladder biopsies and seeded onto preformed bladder-shaped polymers. The native bladders were subsequently excised from canine donors and replaced with the tissue-engineered neo-organs. In functional evaluations for up to 11 months, the bladder neo-organs demonstrated a normal capacity to retain urine, normal elastic properties, and histologic architecture. This study demonstrates, for the first time, that successful reconstitution of an autonomous hollow organ is possible using tissue-engineering methods.

Continuous release of endostatin from microencapsulated engineered cells for tumor therapy.

Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.

Ibuprofen loaded PLA nanofibrous scaffolds increase proliferation of human skin cells in vitro and promote healing of full thickness incision wounds in vivo.

This article presents successful incorporation of ibuprofen in polylactic acid (PLA) nanofibers to create scaffolds for the treatment of both acute and chronic wounds. Nanofibrous PLA scaffolds containing 10, 20, or 30 wt % ibuprofen were created and ibuprofen release profiles quantified. In vitro cytotoxicity to human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) of the three scaffolds with varying ibuprofen concentrations were evaluated and compared to pure PLA nanofibrous scaffolds. Thereafter, scaffolds loaded with ibuprofen at the concentration that promoted human skin cell viability and proliferation (20 wt %) were evaluated in vivo in nude mice using a full thickness skin incision model to determine the ability of these scaffolds to promote skin regeneration and/or assist with scarless healing. Both acellular and HEK and HDF cell-seeded 20 wt % ibuprofen loaded nanofibrous bandages reduced wound contraction compared with wounds treated with Tegaderm™ and sterile gauze. Newly regenerated skin on wounds treated with cell-seeded 20 wt % ibuprofen bandages exhibited significantly greater blood vessel formation relative to acellular ibuprofen bandages. We have found that degradable anti-inflammatory scaffolds containing 20 wt % ibuprofen promote human skin cell viability and proliferation in vitro, reduce wound contraction in vivo, and when seeded with skin cells, also enhance new blood vessel formation. The approaches and results reported here hold promise for multiple skin tissue engineering and wound healing applications. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 327-339, 2017.

The effect of thrombin on ACL fibroblast interactions with collagen hydrogels.

Premature loss of provisional scaffold formation has been identified as one of the factors responsible for poor healing of intraarticular tissues. To address this deficiency, substitute provisional scaffolds are being developed. The function of these scaffolds can be enhanced by the addition of specific extracellular matrix proteins. In this study, it was hypothesized that the addition of thrombin to a provisional scaffold material would result in increases in cell proliferation, collagen production, and cell migration within the scaffold. These three parameters are thought to be critical components of wound healing. Gels containing fibrin and collagen supplemented with either 0, 10.5, 21, or 42 U/mL of thrombin were placed in contact with explants of tissue from the anterior cruciate ligament. The addition of thrombin stimulated cell migration at low concentrations and impaired migration at higher concentrations, and had no significant effect on cell proliferation or collagen production. The use of all concentrations of thrombin resulted in mechanically weaker gels. Thus, the use of thrombin to optimize a collagen-platelet rich plasma (PRP) provisional scaffold must be done with caution, and use of high concentrations of thrombin (>42 IU/mL) should be avoided specifically in situations where gel strength or cell ingrowth is important. Use of low concentrations of thrombin (10.5 IU/mL) may be beneficial in applications where a faster set time and enhanced cell migration are desirable and the gel mechanical strength is of secondary importance.

Sibling vesicoureteral reflux in multiple gestation births.

BACKGROUND: Vesicoureteral reflux (VUR) is the most commonly inherited disease of the genitourinary tract. Although the majority of evidence supports a genetic cause, the tendency for this condition to spontaneously improve over time has made it difficult to determine the actual mode of transmission. We report the incidence of VUR in siblings of multiple gestation births and for the first time compare the relative incidence of reflux between identical and fraternal twins. METHODS: A database consisting of all radionuclide cystograms and voiding cystourethrograms performed between the years 1986 and 1996 was searched for multiple gestation births. The medical records of each patient were evaluated for age at presentation, zygosity, reflux grade, and time to resolution. Children with secondary causes of VUR (eg, posterior urethral valves) were excluded. Triplets were treated as 2 pairs of twins for statistical analysis. RESULTS: Forty-six pairs met the inclusion criteria (31 dizygotic and 15 monozygotic). Overall, 23 (50%) of 46 siblings of index cases had demonstrable VUR. Comparison of VUR prevalence between identical and nonidentical twins was revealing with 80% (12/15) of identical twins and 35% (11/31) of fraternal twins having VUR. When only the youngest individuals in each group were considered, 100% (7/7) of the monozygotics and 50% (5/10) of the dizygotics demonstrated this trait. CONCLUSIONS: High concordance for VUR in identical twin siblings supports a genetic basis for the transmission of this disease. Results obtained from fraternal twin siblings provides convincing evidence that this trait is transmitted in an autosomal dominant fashion.

Tissue engineering: biomedical applications.

This paper discusses a novel approach to tissue engineering involving seeding mammalian cells onto biodegradable polymer scaffolds, growing the cells on these scaffolds in vitro, and then implanting the cell-polymer constructs in vivo. Approaches for in vitro cultivation of cells are first discussed. The types of polymer scaffolds that are utilized and the kinds of bioreactor conditions for growing cells are then delineated. The application of this approach in vitro and in vivo for producing cartilage, tendon, liver, urothelial tissue, intestine, and bone are then examined.

Detection of human androgen receptor mRNA expression abnormalities by competitive PCR.

A competitive polymerase chain reaction (PCR) method for analysis of androgen receptor (AR) mRNA expression is described. The technique involves the use of an in vitro-transcribed RNA (cRNA) corresponding to a region of the AR mRNA transcript as a competitor in reverse transcription and PCR (RT-PCR) using total cellular RNA. The competitor RNA contains a site-directed mutation that produces a restriction fragment length polymorphism after RT-PCR and endonuclease digestion. We demonstrate that incorporation of the competitor RNA into RT-PCR reactions allows rapid semiquantitative determination of relative AR mRNA levels without the necessity of following PCR product formation kinetically; reaction products are assessed at the conclusion of the reaction sequence and without the use of radioactive probes or other specialized detection systems. We have used competitive PCR to demonstrate low levels of AR mRNA in an androgen-unresponsive human prostate cell line (PC3). In addition, we have also used this method to confirm that genital fibroblasts obtained from a subject with penoscrotal hypospadias (a non-intersex masculinization defect) that exhibit low levels of high-affinity androgen binding also exhibit abnormally low AR mRNA levels. These last results suggest that some non-intersex malformations of the urogenital tract are associated with abnormalities in the expression of the androgen receptor.

Endoscopic substances for the treatment of vesicoureteral reflux.

The endoscopic treatment of reflux, like that of urinary incontinence, is effective. Several materials and endoscopic delivery systems are currently under evaluation for the treatment of reflux and incontinence. These include silicone microimplants, glass particles, collagen, dextranomer microspheres, a detachable balloon system, chondrocytes, and muscle cells. Although the endoscopic treatment is rendered in a similar fashion for both urinary incontinence and reflux, the acceptable safety and efficacy parameters of the bulking agents may differ, depending on the condition treated and the age of the patient. A review of the endoscopic bulking substances and systems currently available is presented.

Diethylstilbestrol in treatment of postorchiectomy vasomotor symptoms and its relationship with serum follicle-stimulating hormone, luteinizing hormone, and testosterone.

Vasomotor symptoms such as hot flushes and profuse sweating have been described after bilateral orchiectomy. We evaluated 26 patients who had undergone bilateral orchiectomy for prostatic carcinoma to determine the incidence of vasomotor symptoms and the efficacy of low-dose diethylstilbestrol (DES) in the treatment of those symptoms. Measurements of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were performed to look for endocrine patterns which may be related to the presence of vasomotor symptoms. Fourteen patients (54%) reported the presence of vasomotor symptoms beginning one to four weeks after surgery. These patients were treated with DES or placebo in a double-blind crossover trial. The frequency and severity of hot flushes were significantly reduced during the time DES was given. This was accomplished with a low dose of 1 mg daily of DES which avoids the cardiovascular complications of higher doses. We found no correlation between the presence, severity, or frequency of hot flushes and serum gonadotropin or testosterone concentrations.

Extracorporeal shock-wave lithotripsy in transplanted kidney.

Urolithiasis is the least described urologic sequela of renal transplantation. We describe a renal transplant patient who presented with painless gross hematuria. An intravenous pyelogram demonstrated a 4 x 7-mm calculi in the region of the ureteropelvic junction, causing moderate hydronephrosis. The patient was treated successfully with extracorporeal shock-wave lithotripsy (ESWL). Serum creatinine and twenty-four-hour creatinine clearance were unchanged from levels prior to ESWL.

Bladder augmentation using allogenic bladder submucosa seeded with cells.

OBJECTIVES: The search for a suitable material to reconstruct the genitourinary tract has been a challenging task. Bowel has been widely used for urinary tract reconstruction, despite its subsequent complications. We investigated the possibility of using allogenic bladder submucosa, a tissue consisting of nonimmunogenic acellular collagen, either with or without cells, as a material for bladder augmentation. METHODS: Partial cystectomies were performed in 10 beagle dogs. Both urothelial and smooth muscle cells were harvested and expanded separately in 5 animals. The allogenic bladder submucosa obtained from sacrificed dogs was seeded with muscle cells on one side and urothelial cells on the opposite side. All beagles underwent cruciate cystotomies on the bladder dome. Augmentation cystoplasty was performed with the allogenic bladder submucosa seeded with cells in 5 animals and with the allogenic bladder submucosa without cells in 5. The augmented bladders were retrieved 2 and 3 months after augmentation. RESULTS: Bladders augmented with the allogenic bladder submucosa seeded with cells showed a 99% increase in capacity compared with bladders augmented with the cell-free allogenic bladder submucosa, which showed only a 30% increase in capacity. All dogs showed a normal bladder compliance, as evidenced by urodynamic studies. Histologically, all retrieved bladders contained a normal cellular organization consisting of a urothelial lined lumen surrounded by submucosal tissue and smooth muscle. Immunocytochemical analyses confirmed the urothelial and muscle cell phenotype and showed the presence of nerve fibers. CONCLUSIONS: These results show that allogenic bladder submucosa seeded with cells appears to be an excellent option as a biomaterial for bladder augmentation.

Priapism associated with asplenic state.

Priapism may be primary (idiopathic) or secondary to sickle cell anemia, trauma, leukemia, drugs, venous thromboembolic diseases, and other less common disorders. This study concerns 21 patients with priapism treated during a period of ten years. Nine patients (43%) had sickle cell anemia. Of the 12 individuals (57%) classified as idiopathic, 3 (25%) had previously undergone surgical splenectomy for benign conditions. Considering the propensity for this unusual condition to develop in patients with hemoglobinopathy-induced hyposplenism, the possibility of a relationship between the asplenic state and priapism is considered.

Urachal anomalies: defining the best diagnostic modality.

OBJECTIVES: Urachal abnormalities are uncommon and the literature is primarily comprised of case reports. Conclusions regarding the presentation and diagnosis of these abnormalities may be elucidated by reviewing a large experience. METHODS: The records of 45 patients with urachal abnormalities in the pediatric age group were reviewed from 1970 to 1997. This included 24 boys and 21 girls with an age range from 1 day to 20 years (average 4.0 years). The presenting complaint was periumbilical discharge in 19 patients (42%), umbilical cyst or mass in 15 (33%), abdominal or periumbilical pain in 10 (22%), and dysuria in 1 (2%). The diagnosis consisted of a urachal sinus in 22 children (49%), a urachal cyst in 16 (36%), and a patent urachus in 7 (15%). Various radiographic studies were used to establish the diagnosis. RESULTS: Patients with a urachal sinus had 16 voiding cystourethrograms performed (only 1 diagnostic), 9 sinograms (all diagnostic), 8 ultrasounds (4 diagnostic), and 1 excretory urogram (normal). Those with a urachal cyst had 8 voiding cystourethrograms (1 diagnostic), 5 excretory urograms (all normal), 4 ultrasounds (all diagnostic), and 1 computed tomography scan (diagnostic). Children with a patent urachus had 2 excretory urograms (both diagnostic), 1 voiding cystourethrogram (diagnostic), and 2 ultrasounds (normal). One baby with a patent urachus was diagnosed prenatally during ultrasound screening. The diagnosis was made by history and physical examination alone in 5 children and at the time of surgery in 1. Treatment consisted of surgical excision of the urachal abnormality with a cuff of bladder in 22 children, surgical excision without a bladder cuff in 22, incision and drainage of a urachal cyst (1%), and laparoscopic excision of a patent urachus with a bladder cuff in another (1%). There were three wound infections postoperatively. None developed any long-term sequelae. CONCLUSIONS: The diagnosis of urachal abnormalities can be made with certainty if a good physical examination and the appropriate radiographic test are performed. A patient who presents with periumbilical drainage should have a sinogram performed, which should be diagnostic for both a urachal sinus and a patent urachus. Any child who presents with a periumbilical mass should have an ultrasound performed, which should be diagnostic for a urachal cyst.

Alterations in angiogenic growth factors and neuronal nitric oxide synthase expression in chronic cavernosal ischemia.

Our aim was to study anatomical and molecular changes at varying time points after the induction of cavernosal ischemia (CI) in a rabbit model of arteriogenic erectile dysfunction. Tissue structure and the expression of angiogenic and neurogenic genes were examined using immunostaining and reverse transcription-polymerase chain reaction (RT-PCR) analyses. We found a progressive increase of erectile connective tissue together with a decrease in smooth muscle cell content as the duration of CI increased. Immunohistochemical staining showed an increase in vascular endothelial growth factor (VEGF) levels at the early stages and a decrease at the later stages of ischemia. RT-PCR analysis of VEGF and neuronal nitric oxide synthase (nNOS) confirmed these results and showed nearly a two-fold increase in VEGF and nNOS mRNA levels in the early stages of CI with a decrease at the later stages of CI. On the other hand, mRNA levels of VEGF receptor, KDR, decreased approximately by 50% over the course of CI. Our studies showed that the cellular and molecular responses of the erectile tissue to short-term ischemia are different than those seen after long-term ischemia. The dramatic reduction in KDR expression suggests that the cavernosal endothelium is very sensitive to ischemia. The similar changes in VEGF and nNOS expression over the course of CI suggest a tissue-defensive mechanism to CI via the VEGF and NO pathways. Taken together, this study suggests that supplementation of VEGF at earlier stages of ischemia may restore the damaged endothelial cells of the corpus cavernosum and support tissue perfusion.