Complications and Interventions in Patients with an Artificial Urinary Sphincter: Long-Term Results.

PURPOSE: The artificial urinary sphincter is a common treatment of male urinary incontinence. We sought to characterize long-term rates of artificial urinary sphincter revision/removal and reimplantation, and associated risk factors. MATERIALS AND METHODS: We performed a population based, retrospective study using the Ontario Health Insurance Plan database of all male patients who underwent artificial urinary sphincter implantation from 1994 to 2013. Hospital, diagnostic and billing codes were used to identify patients. The Kaplan-Meier method and multivariable Cox proportional hazards models were applied to examine the cumulative incidence of artificial urinary sphincter reimplantation and revision/removal, and identify risk factors, respectively. RESULTS: A total of 1,632 male patients underwent initial implantation of an artificial urinary sphincter. The 10-year revision/removal and reimplantation rates were 34% and 27%, respectively. There was no difference between high and low volume hospitals or between community and academic hospitals in terms of revision/removal. A high level of comorbidity was associated with an increasing risk of removal/revision. The reimplantation rate was significantly lower in patients who underwent insertion at hospitals with the highest volume of surgery (HR 0.55, 95% CI 0.37-0.82, p <0.01). A high level of comorbidity was not associated with an increasing risk of reimplantation. Preimplantation radiotherapy was not significantly associated with the risk of reimplantation (p = 0.17) or revision/removal (p = 0.95). Other factors were not significantly associated with reimplantation or revision/removal. CONCLUSIONS: Most men who undergo artificial urinary sphincter placement still have a device without repeat surgery 10 years following insertion. Radiotherapy does not increase the risk of repeat surgery. A high level of comorbidity was associated with an increasing risk of removal/revision.

Comparing a novel hand held device (Peritron+) to standard urodynamics in measuring intravesical pressure.

AIMS: Peritron+ is a new handheld device, which can be attached to a urethral catheter to measure intravesical pressures (Pves). The goal of this study was to assess if Pves recorded by standard urodynamics (UDs) are comparable to those recorded by the Peritron+. METHODS: Patients with voiding dysfunction and an indication for UD underwent measurement of Pves with nonvideo UD and Peritron+. Pves were recorded at volumes of 50, 100, and 200 mL for the supine and sitting positions. A failure of the Peritron+ was considered to be a discrepancy of Pves values >3 cmH2 O between Peritron+ and UD recordings. Two-way ANOVA was used to assess for statistical significance. P-values < 0.05 were considered significant. RESULTS: Ten female patients, mean age 51 years old, were enrolled in the study. The difference in Pves measurements between Peritron+ and UD were ≤3 cmH2 O at all bladder volumes measured in a supine and sitting positions. There were no adverse events and there were no malfunctions of the Peritron+ device during the study. CONCLUSIONS: Peritron+ handheld device accurately assessed Pves at different intravesical volumes when compared to UD measurements. The Peritron+ is a simple and safe device, which can be used in the office by a clinician and at home by a patient to monitor Pves and help to select patients who may require standard UD re-evaluation. This will be a valuable tool in managing patients with neurogenic and nonneurogenic bladders who are at a risk of upper urinary tract deterioration.

Impact of resident involvement in endoscopic bladder cancer surgery on pathological outcomes.

OBJECTIVE: Transurethral resection of bladder tumor (TURBT) pathology specimens which lack muscle are associated with clinical upstaging and may necessitate repeat resections, potentially delaying curative treatment. This study evaluated whether resident involvement in TURBT is associated with suboptimal perioperative outcomes. MATERIALS AND METHODS: All TURBTs performed at a Canadian healthcare institution from November 2011 to June 2014 were reviewed. Multivariable logistic regression models assessed associations between intraoperative resident involvement and TURBT muscle presence. Among high-risk patients (high grade, ≥ T1 or carcinoma in situ) who underwent cystectomy, time from TURBT to cystectomy was compared between resident and attending urologists with the log-rank test. RESULTS: In total, 463 TURBTs were identified. In multivariable analyses, residents were less likely to obtain muscle in specimens for all TURBTs [adjusted odds ratio (aOR) 0.59, p = 0.03] and the subset of 275 high-risk TURBTs (aOR 0.41, p = 0.006). Among patients who underwent cystectomy, time to cystectomy was delayed by a median of 23 days when residents were involved in the initial high-risk TURBT compared with attending urologists only (p = 0.024). CONCLUSIONS: In this single academic center series, intraoperative resident involvement was associated with a decreased rate of muscle presence in TURBT specimens and a prolonged time to cystectomy.

Paradoxical air embolism during percutaneous nephrolithotomy due to patent foramen ovale: Case report.

Paradoxical air embolism is a very rare complication associated with percutaneous nephrolithotomy (PCNL). Incidence may be higher if patients also suffer from a septal heart defect. We report the case of a 76-year old male who presented for PCNL treatment of a right kidney lower calyceal calculus. During the procedure, the patient developed signs and symptoms consistent with that of air embolism. Intraoperative echocardiography confirmed the diagnosis. Subsequent intraoperative and postoperative medical management was carried out and the patient was discharged after recovery three days later. This case highlights the importance of a rare but potentially fatal complication of PCNL.

Angiosarcoma of the adrenal gland with concurrent contralateral advanced renal cell carcinoma: A diagnostic and management dilemma.

Angiosarcoma is a rare high-grade malignant neoplasm with poor clinical outcome and survival rates, occurring most commonly in the skin and soft tissue. It is composed of neoplastic cells that demonstrate endothelial differentiation. The diagnosis of angiosarcoma can be difficult due to its pathohistologic presentation as a poorly differentiated neoplasm with associated secondary changes. We report a case of angiosarcoma of the adrenal gland with concurrent contralateral renal cell carcinoma (RCC) and renal vein thrombus. The presumptive clinical diagnosis was metastatic renal cell carcinoma to the contralateral adrenal gland. Pathohistologic evaluation demonstrated massive hematoma associated with intravascular papillary endothelial hyperplasia (IPEH)-like features. We discuss the pathohistological features used to ascertain a diagnosis of angiosarcoma in the presence of IPEH-like changes and differentiate it from reactive vascular proliferation seen in IPEH (Masson's tumour).

Evaluating practice patterns in postnatal management of antenatal hydronephrosis: a national survey of Canadian pediatric urologists and nephrologists.

OBJECTIVE: To ascertain practice patterns of prescribing continuous antibiotic prophylaxis (CAP) and obtaining a voiding cystourethrogram for infants with antenatal hydronephrosis (AHN) by pediatric nephrologists and urologists across Canada. METHODS: A previously piloted online survey was distributed to members of the Canadian pediatric nephrology and urology associations. Summarized confidential responses were stratified by specialty, AHN grade, and laterality. RESULTS: A total of 88 of 139 responses were received (response rate, 63.3%; 95% confidence interval, 55.0%-71.0%): 46 nephrologists, 39 urologists, and 3 undisclosed. Only 17 of 88 (19.32%; 95% confidence interval, 12.4%-28.8%) reported following standardized AHN protocols. Concern surrounding the development of urinary tract infections was the main deciding factor for prescribing CAP (nephrology, 65.4%; urology, 71.4%). Almost a third of nephrologists (29.6%) recommend CAP for bilateral low-grade AHN compared with 11.4% of urologists (P = .02); in contrast, 73% of nephrologists and 38.2% of urologists (P = .02) offer CAP in the presence of isolated high-grade AHN. In regards to indications for voiding cystourethrogram, 31% of pediatric nephrologists would recommend this test for patients with unilateral low-grade AHN compared with 7.7% of urologists (P < .01), although almost all nephrologists (96.6%) and 69.2% of urologists (P = .02) would obtain this test for patients with unilateral high-grade isolated AHN. CONCLUSION: Our results show important practice variability between pediatric nephrologists and urologists in the management of children with AHN, which are partially explained by laterality and degree of dilation. This survey reflects the lack of treatment guidelines and supports efforts to obtain high-level evidence to develop management protocols for this common condition.

Management of a patient with locally advanced prostate cancer with degarelix: a case report.

Gonadotropin releasing hormone (GnRH) antagonists, such as degarelix, are emerging as an androgen deprivation therapy primary agents in a treatment of advanced prostate cancer. The role of GnRH antagonists in management of lower urinary tract symptoms associated with prostate cancer has not been clearly established. In this report, we describe the case of a patient with locally advanced prostate cancer who presented with symptoms of urinary retention and renal failure. The use of degarelix in this patient led to a rapid reduction in the prostate-specific antigen level; however, obstructive symptoms persisted despite the use of degarelix and radiation treatment.

Analysis of the clinical significance and cost associated with the routine pathological analysis of pediatric inguinal hernia sacs.

PURPOSE: Pediatric inguinal and scrotal surgeries for inguinal hernia, cryptorchidism and hydrocele are common and usually involve the excision of a hernia sac. Groups at many centers send hernia sacs for pathological analysis to identify occult disease as well as structures that may have been erroneously resected. We hypothesized that, since the incidence of significant findings is low and the associated health care costs are significant, the routine pathological analysis of inguinal hernia sacs is unnecessary. MATERIALS AND METHODS: After receiving institutional review board approval we retrospectively reviewed pathology reports at our institution of patients who underwent surgery with an inguinal hernia sac sent for pathological analysis from January 2000 to September 2009. The primary outcome was to determine the incidence of clinically significant structures in hernia sac specimens. The secondary outcome was to evaluate the costs associated with analyzing these specimens. RESULTS: A total of 2,287 boys and 441 girls underwent some form of inguinal or scrotal surgery during the study. In the 2,287 boys a total of 2,657 hernia sac specimens were analyzed, of which 2 (0.08%) contained clusters of epididymal-like tubules. Most unexpected findings were likely clinically insignificant, including mesothelial proliferation in 5.6% of cases, genital duct remnants in 0.8%, lipoma in 0.23% and adrenocortical rests in 0.04%. The average cost of analyzing hernia sac specimens at our institution was approximately $7,100 Canadian annually. CONCLUSIONS: Routine analysis of inguinal hernia sacs is unnecessary and costly, and should be reserved for cases in which resection of important structures such as the vas deferens is suspected.

E2F4 is required for early eye patterning.

Increasingly, studies reveal novel functions for cell cycle proteins during development. Here, we investigated the role of E2F4 in eye development. E2F4-deficient mouse embryos exhibit severe early eye patterning defects, which are evident from embryonic day 11.5 and characterized by aberrant shape of the optic cup, coloboma as well as abnormal eye pigmentation. Loss of E2F4 is associated with proximal-distal patterning defects in the optic vesicle. These defects are characterized by the expansion of optic stalk marker gene expression to the optic cup and reduced expression of ventral optic cup markers. These defects are associated with a split of Shh expression domain at the ventral midline of the forebrain and expansion of the Shh activity into the ventral optic cup. Despite these patterning defects, early neuronal differentiation and Shh expression in the retina are not affected by E2F4 deletion. Overall, the results of our studies show a novel role of E2F4 in the early eye development.

Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.

Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development. Neural precursors within the ventricular zone and newly committed neurons in the cortical plate express high levels of Mcl-1 throughout cortical neurogenesis. Loss of Mcl-1 in neuronal progenitors results in widespread apoptosis. Double labeling with active caspase 3 and Tuj1 reveals that newly committed Mcl1 deficient neurons undergo apoptosis as they commence migration away from the ventricular zone. Examination of neural progenitor differentiation in vitro demonstrated that cell death in the absence of Mcl1 is cell autonomous. Although conditional deletion of Mcl-1 in cultured neurons does not trigger apoptosis, loss of Mcl-1 sensitizes neurons to an acute DNA damaging insult. Indeed, the rapid reduction of Mcl-1 mRNA and protein levels are early events after DNA damage in neurons, and maintaining high Mcl-1 levels can protect neurons against death. Together, our results are the first to demonstrate the requirement of Mcl-1, an anti-apoptotic Bcl-2 family protein, for cortical neurogenesis and the survival of neurons after DNA damage.

Cell cycle regulator E2F4 is essential for the development of the ventral telencephalon.

Early forebrain development is characterized by extensive proliferation of neural precursors coupled with complex structural transformations; however, little is known regarding the mechanisms by which these processes are integrated. Here, we show that deficiency of the cell cycle regulatory protein, E2F4, results in the loss of ventral telencephalic structures and impaired self-renewal of neural precursor cells. The mechanism underlying aberrant ventral patterning lies in a dramatic loss of Sonic hedgehog (Shh) expression specifically in this region. The E2F4-deficient phenotype can be recapitulated by interbreeding mice heterozygous for E2F4 with those lacking one allele of Shh, suggesting a genetic interaction between these pathways. Treatment of E2F4-deficient cells with a Hh agonist rescues stem cell self-renewal and cells expressing the homeodomain proteins that specify the ventral telencephalic structures. Finally, we show that E2F4 deficiency results in impaired activity of Shh forebrain-specific enhancers. In conclusion, these studies establish a novel requirement for the cell cycle regulatory protein, E2F4, in the development of the ventral telencephalon.

Unique requirement for Rb/E2F3 in neuronal migration: evidence for cell cycle-independent functions.

The cell cycle regulatory retinoblastoma (Rb) protein is a key regulator of neural precursor proliferation; however, its role has been expanded to include a novel cell-autonomous role in mediating neuronal migration. We sought to determine the Rb-interacting factors that mediate both the cell cycle and migration defects. E2F1 and E2F3 are likely Rb-interacting candidates that we have shown to be deregulated in the absence of Rb. Using mice with compound null mutations of Rb and E2F1 or E2F3, we asked to what extent either E2F1 or E2F3 interacts with Rb in neurogenesis. Here, we report that E2F1 and E2F3 are both functionally relevant targets in neural precursor proliferation, cell cycle exit, and laminar patterning. Each also partially mediates the Rb requirement for neuronal survival. Neuronal migration, however, is specifically mediated through E2F3, beyond its role in cell cycle regulation. This study not only outlines overlapping and distinct functions for E2Fs in neurogenesis but also is the first to establish a physiologically relevant role for the Rb/E2F pathway beyond cell cycle regulation in vivo.

p107 regulates neural precursor cells in the mammalian brain.

Here we show a novel function for Retinoblastoma family member, p107 in controlling stem cell expansion in the mammalian brain. Adult p107-null mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed striking increases in the number of neurosphere forming cells from p107(-/-) brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was shown in vivo by (a) increased numbers of slowly cycling cells in the lateral ventricles; and (b) accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 was up-regulated in p107(-/-) neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggest that p107 may modulate the Notch1 pathway. These results demonstrate a novel function for p107 that is distinct from Rb, which is to negatively regulate the number of neural stem cells in the developing and adult brain.

Protective role of extracellular chloride in fatigue of isolated mammalian skeletal muscle.

A possible role of extracellular Cl(-) concentration ([Cl(-)](o)) in fatigue was investigated in isolated skeletal muscles of the mouse. When [Cl(-)](o) was lowered from 128 to 10 mM, peak tetanic force was unchanged, fade was exacerbated (wire stimulation electrodes), and a hump appeared during tetanic relaxation in both nonfatigued slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles. Low [Cl(-)](o) increased the rate of fatigue 1) with prolonged, continuous tetanic stimulation in soleus, 2) with repeated intermittent tetanic stimulation in soleus or EDL, and 3) to a greater extent with repeated tetanic stimulation when wire stimulation electrodes were used rather than plate stimulation electrodes in soleus. In nonfatigued soleus muscles, application of 9 mM K(+) with low [Cl(-)](o) caused more rapid and greater tetanic force depression, along with greater depolarization, than was evident at normal [Cl(-)](o). These effects of raised [K(+)](o) and low [Cl(-)](o) were synergistic. From these data, we suggest that normal [Cl(-)](o) provides protection against fatigue involving high-intensity contractions in both fast- and slow-twitch mammalian muscle. This phenomenon possibly involves attenuation of the depolarization caused by stimulation- or exercise-induced run-down of the transsarcolemmal K(+) gradient.