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The diagnosis of bladder outlet obstruction in men by ultrasound measurement of bladder wall thickness.

PURPOSE: The objective of the study was to investigate specificity and sensitivity of bladder wall thickness in the diagnosis of bladder outlet obstruction. MATERIALS AND METHODS: The study included 174 patients referred to our prostate centers for lower urinary tract symptoms. Free uroflowmetry and pressure-flow studies were performed in duplicate as part of the diagnostic evaluation. After the 2 voiding studies were done the bladder was filled to 150 ml. and wall thickness was measured via suprapubic ultrasound. Bladder outlet obstruction was diagnosed and graded according to the Abrams-Griffiths and Schäfer nomogram as well as to the group specific urethral resistance algorithm. RESULTS: A significant correlation (r > 0.6, p < or = 0.007) was found between bladder wall thickness and all parameters of the pressure-flow study. A bladder wall thickness of 5 mm. appeared to be the best cutoff point to diagnose bladder outlet obstruction, since 63.3% of patients with bladder wall thickness less than 5 mm. were unobstructed while 87.5% of those with a bladder wall thickness 5 mm. or greater were obstructed. Bladder wall thickness out performed uroflowmetry in terms of specificity and sensitivity in the diagnosis of outlet obstruction as demonstrated by an area under curve value of 0.860 versus 0.688 in the receiver operator characteristics analysis. CONCLUSIONS: Measurement of bladder wall thickness appears to be a useful predictor of outlet obstruction with a diagnostic value exceeding free uroflowmetry although it does not represent a substitution to invasive urodynamics. These data support the hypothesis that the relationships between morphology and function are of clinical importance.

Adult↗

Telomerase: a potential marker of bladder transitional cell carcinoma in bladder washes.

Telomerase is an enzyme that immortalizes cells by maintaining a constant telomere length. Here, telomerase activity in bladder washes was analyzed and compared with the final pathological diagnosis in 23 patients with bladder transitional cell carcinoma (TCC). Bladder washes and normal tissues were obtained from each patient prior to transurethral resection of bladder tumor. Telomerase activity was detected using telomeric repeat amplification protocol assay based on PCR. Cytological diagnosis of centrifuged cells from bladder washes was made using Papanicolau's stain. Results demonstrated that telomerase activity was detected in 95.7% of both cancer tissues and bladder washes. In normal tissues, telomerase activity was not detected in 22 of 23 samples. Regarding cytological diagnosis, only 69.6% of bladder wash samples had positive cytology. Moreover, in five cases of grade 1 TCC, only 20% of the cytological specimens were positive for malignancy, whereas 80% showed positive telomerase activity. These results demonstrate that telomerase activity is detectable in a majority of human bladder cancer tissues and bladder washes obtained from patients with TCC. In addition, results of this study suggest that the presence of telomerase in bladder washes may be a specific marker of bladder cancer, especially in low-grade tumors.

Aged↗

Biodistribution of Photofrin II and 5-aminolevulinic acid-induced protoporphyrin IX in normal rat bladder and bladder tumor models: implications for photodynamic therapy.

Photodynamic therapy (PDT) has been considered as a potential therapy for superficial bladder carcinomas. Cutaneous photosensitivity and reduction of bladder capacity are the two well-known complications following systemic administration of the commonly used photosensitizer, Photofrin II (PII). The objective of the present study was to evaluate whether intravesical (i.b.) instillation of photosensitizers for PDT of bladder cancer might be a more suitable treatment method. Female Fischer rats were utilized to develop orthotopic and heterotopic bladder tumor models. Rats bearing orthotopic bladder tumors were treated either intravesically or intravenously with graded doses of 5-aminolevulinic acid (ALA) or PII. Normal rats received the same doses of ALA or PII. As well, rats bearing heterotopic tumor were studied for comparison. The biodistribution times (times allowed for tissue uptake and bioconversion following drug administration) were 2, 4 or 6 h. Porphyrin fluorescence intensities within tumor, urothelium, submucosa, bladder muscularis and abdominal muscle were quantitated by confocal laser scanning microscopy. Following intravenous (i.v.) injection of ALA, tumor protoporphyrin IX (PpIX) levels peaked at 4 h and diminished by 6 h. The PpIX ratios of tumor-to-bladder mucosa, submucosa and muscle layers were 3:1, 5:1 and 8:1, respectively, 4 h following 1000 mg/kg ALA injection. After ALA instillation, the optimal biodistribution time appeared to be 4 h. Bladder instillation provided comparable tumor labeling with the i.v. route, but lost selectivity of PpIX accumulation between tumor and normal urothelium. The PpIX ratio of tumor-to-bladder muscularis was 5:1. After i.b. instillation of PII, porphyrin fluorescence was detected only within tumor and urothelium, while porphyrin fluorescence was mainly located in bladder submucosa following i.v. injection. Intravesical administration of ALA or PII might be feasible for PDT of superficial bladder cancers.

Aminolevulinic Acid↗

Living-related partial bladder transplantation for bladder augmentation in rats: an experimental study.

PURPOSE: To assess the feasibility of transplanting adult bladder tissue to its offspring as a source of neobladder tissue for bladder augmentation. METHODS: The dome of the bladder of an adult Lewis rat was excised and transplanted into the omentum of a 6-week-old offspring (living-related partial bladder transplant: n = 15). The bladder remnant of the donor rat was closed. Two weeks after transplantation, a laparotomy was performed to mobilize the bladder graft with its omental pedicle into the pelvis. Bladder augmentation (BA) was performed by anastomosing the graft to the recipient's bladder. Thirty days after BA, the entire neobladder was excised and histopathologically examined. RESULTS: At laparotomy, each bladder graft appeared macroscopically as a thin-walled cyst in the recipient's omentum. Each graft could be mobilized into the pelvis and anastomosed to the recipient's bladder. BA was successful in all 15 recipients, and histopathologic studies showed that the mucosa was normal throughout each neobladder. Postoperatively, donors and recipients were clinically well without any sign of urinary incontinence or obstruction. CONCLUSIONS: This is the first report of adult tissue being transplanted successfully into a recipient without vascular reconstruction in a rat. Living-related partial bladder transplantation for the purpose of BA is feasible using our technique and could have application as an alternative technique for BA in a rat.

Anastomosis, Surgical↗

Clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder.

PURPOSE: The effect of bladder cancer histological subtypes other than transitional cell carcinoma (nonTCC) on clinical outcomes remains uncertain. We conducted a multi-institutional retrospective study of patients with bladder cancer treated with radical cystectomy to assess the impact of nonTCC histology on bladder cancer specific outcomes. MATERIALS AND METHODS: A total of 955 consecutive patients underwent radical cystectomy with bilateral pelvic lymphadenectomy for bladder cancer at 3 academic institutions. TCC was present in the radical cystectomy specimen in 888 patients (93%). NonTCC histology was present in 67 patients (7%), including squamous cell carcinoma in 26, adenocarcinoma in 13, small cell carcinoma in 10 and other nonTCC subtypes (ie spindle cell carcinoma, carcinosarcoma and undifferentiated carcinoma) in 18. For patients alive at last followup median followup was 39 and 23 months for patients with TCC and nonTCC histologies, respectively. Bladder cancer specific progression and survival were assessed using Kaplan-Meier and multivariate Cox proportional hazards analyses. RESULTS: Bladder cancer specific progression and mortality did not differ significantly between patients with SCC and TCC histologies. Patients with nonTCC and nonSCC bladder cancer were at significantly increased risk for progression and death compared to patients with TCC or SCC (p <0.001). This association remained statistically significant in patients with organ confined disease (stage pT2 or lower) and patients with nonorgan confined disease (stage pT3 or higher) (p <0.001). In a multivariate analysis nonTCC and nonSCC histology was associated with an increased risk of bladder cancer progression and death (OR 2.272 and 2.585, respectively, p <0.001), even after adjusting for final pathological stage, lymph node status, lymphovascular invasion and neoadjuvant or adjuvant treatments. CONCLUSIONS: NonTCC and nonSCC histological subtype is an independent predictor of bladder cancer progression and mortality in patients undergoing radical cystectomy for bladder cancer. Patients with bladder TCC and SCC share similar stage specific clinical outcomes.

Aged↗

Bladder filling in mice: an experimental in vivo model to evaluate the reservoir function of the urinary bladder in a long term study.

We report a simple, reproducible, and low-invasive in vivo method for repeated examination of bladder well properties in mice. Over a period of 21 days transurethral bladder fillings were performed every second day on the same animal. Analysis of the bladder volume at an intravesical pressure of 10 and 20 mm. Hg and at the leakage point showed no trend during the 21 day study period with regard to changes in bladder volume. The model has been applied to a group of mice treated with a single fraction bladder irradiation dose of 20 Gy. These mice were investigated repeatedly during the following year. The end point selected for data evaluation in the irradiated group of mice was a 50% decrease in bladder volume at an intravesical pressure of 20 mm. Hg relative to the control value (bladder volume before irradiation). The results clearly demonstrate a biphasic change in the bladder reservoir function, in the form of an acute, reversible change, a period of normalization and then a late irreversible damage. The latter stage is consistent with the clinically found contracted bladder. In a control group there was no significant change in bladder volume during the study period of more than 200 days. The model thus appears feasible for future studies of bladder irradiation damage.

Animals↗

Dynamic evaluation of absorbed dose to the bladder wall with a balloon-bladder phantom during a study using [(18)F]fluorodeoxyglucose positron emission imaging.

An accurate evaluation of the absorbed dose to the bladder wall from 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) is clinically important because the bladder is considered as a critical organ in most positron emission tomography (PET) studies that cumulate about 20% of the total activity injection during image procedures. In the MIRD calculation, no allowance is made for the inclusion of all the dynamic parameters that affect the actual dose to the bladder wall to be taken in the dose assessment. The goal of the study is to propose a dose evaluation model by using a dynamic bladder phantom and time-activity curves from the bladder PET imaging. The proposed model takes all dynamic parameters into account and provides a much more accurate dose estimation to the bladder. In this study, the lowest dose to the bladder wall was obtained at the conditions of having a larger initial volume for the bladder contents and a higher production rate for urine. It is then advised patients to drink a bulk amount of water before the FDG injection or after urine voiding to facilitate urine production and to enlarge the bladder surface area, which are the most crucial steps in reducing the dose to the bladder wall. In our study, the voiding schedule in dose calculation plays certain roles although it is much more critical in the conventional MIRD calculation. The model estimated that the lowest dose to the bladder would occur at an initial void about 40 min after the FDG injection and the urine voiding was as complete as possible.

Adult↗

Delayed treatment of bladder outlet obstruction after sling surgery: association with irreversible bladder dysfunction.

PURPOSE: Our urethrolysis cohort demonstrated an unusual delay time to surgical treatment of bladder outlet obstruction. We determined whether urethrolysis outcomes, ie persistent bladder symptoms, were associated with time between sling and urethrolysis surgeries. MATERIALS AND METHODS: Retrospective analysis of all patients who underwent urethrolysis for post-sling voiding dysfunction between June 1997 and June 2002 was performed. We excluded from study 6 patients with a known history of overactive bladder symptoms, neurogenic bladder dysfunction and use of anticholinergic pharmacotherapy before stress incontinence surgery. The remaining 15 patients were stratified into 2 outcomes groups based upon the absence or presence of post-urethrolysis bladder storage symptoms. Patients (7) in group 1 have no current bladder symptoms. Patients (8) in group 2 still require anticholinergic drug therapy for significant bladder symptoms of frequency and urgency. Data collected for the 2 groups included mean age, existence of urinary retention before urethrolysis, mean time to urethrolysis in months, urethrolysis outcome based upon subjective bladder symptoms and followup duration. For comparison of mean age between groups the standard t test was used. Fisher's exact test was used to compare frequency of urinary retention before urethrolysis between groups. Lastly the Mann-Whitney U test was conducted to compare time to urethrolysis between groups. All statistical analyses were conducted using the SPSS software package (SPSS, Inc., Chicago, Illinois). RESULTS: There was no statistically significant difference between the groups with respect to age or frequency of urinary retention before urethrolysis. Time to urethrolysis for the whole cohort ranged from 2 to 66 months. Mean followup after urethrolysis was 17.3 +/- 22.9 months. Comparison of mean time between incontinence and urethrolysis surgeries between group 1 (9.0 +/- 10.1 months) and group 2 (31.25 +/- 21.9 months) demonstrated a statistically significant difference (p = 0.01). CONCLUSIONS: This urethrolysis population demonstrated an unusual delay time to surgical treatment of bladder outlet obstruction. We categorized the cohort according to absence or presence of persistent bladder storage symptoms, and found a strong association between persistent bladder symptoms and greater delay to urethrolysis.

Aged↗

Analytical and clinical evaluation of a new urinary tumor marker: bladder tumor fibronectin in diagnosis and follow-up of bladder cancer.

Bladder cancer is the fourth most common malignant neoplasm in men and the tenth most common in women. Cystoscopy presents the gold standard for detection and monitoring of bladder cancer. However, it is an invasive and expensive procedure. Therefore, development of biomarkers for the purposes of screening, diagnosis and prediction of the prognosis in bladder cancer is required. Bladder tumor fibronectin is one of the new urinary tumor markers. The aim of this study is to evaluate the diagnostic performance of urinary bladder tumor fibronectin in detecting and monitoring bladder cancer. A total of 75 patients with the diagnosis of bladder cancer, 20 patients with the diagnosis of benign prostatic hyperplasia, 7 patients with the diagnosis of prostate cancer between the years 1996-2000, and 28 age-matched healthy individuals, were enrolled in the study. The patients were diagnosed by cystoscopy, with histopathological evaluation of the tumor, as having superficial or invasive bladder cancer. Patients were followed-up clinically with data pertinent to disease recurrence and progression. Bladder tumor fibronectin (BTF; ng/ml) was determined by solid phase, two-site chemiluminescent immunometric commercial diagnostic assay developed for the Immulite automated immunoassay system (Diagnostic Products Corporation, Los Angeles, CA, USA). All measured values were normalized by urinary creatinine, and the obtained data were evaluated by receiver-operating characteristics (ROC) curve analysis. Optimal cut-off was established at 43.4 ng/mg. This cut-off rendered overall sensitivities of 72% and specificity of 82.1%. The analytical evaluation of the BTF test displayed promising results in terms of a non-invasive in vitro test in the diagnosis of bladder cancer. Although it was not satisfactory in prediction of recurrence or progression of the disease, it correlated well with the stage, one of the most reliable prognostic factors. In conclusion, the urinary bladder tumor fibronectin test warrants further clinical evaluation.

Biomarkers, Tumor↗

The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.

PURPOSE: To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m(2) i.v. and 5-fluorouracil (5-FU) 400 mg/m(2) i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months. RESULTS: Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment. CONCLUSION: This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

Adult↗

Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.

The properties of bladder afferent neurons in L6 and S1 dorsal root ganglia of adult rats were evaluated after chronic bladder inflammation induced by 2 week treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp recordings revealed that most (70%) of the dissociated bladder afferent neurons from control rats were capsaicin sensitive, with high-threshold long-duration action potentials that were not blocked by tetrodotoxin (TTX; 1 microM). These neurons exhibited membrane potential relaxations during voltage responses elicited by depolarizing current pulses and phasic firing during sustained membrane depolarization. After CYP treatment, a similar proportion (71%) of bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes. However, the neurons were significantly larger in size (diameter 29.6 +/- 1.0 micrometer vs 23.6 +/- 0.8 micrometer in controls). TTX-resistant bladder afferent neurons from CYP-treated rats exhibited lower thresholds for spike activation (-25.4 +/- 0.5 mV) than those from control rats (-21.4 +/- 0.9 mV) and did not exhibit membrane potential relaxation during depolarization. Seventy percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited tonic firing (average 12.3 +/- 1.4 spikes during a 500 msec depolarizing pulse) versus phasic firing (1.2 +/- 0.2 spikes) in normal bladder afferent neurons. Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent neurons mimicked the changes in firing properties after CYP treatment. The peak density of an A-type K+ current (IA) during depolarizations to 0 mV in TTX-resistant bladder afferent neurons from CYP-treated rats was significantly smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the inactivation curve of the IA current was displaced to more hyperpolarized levels by approximately 15 mV after CYP treatment. These data suggest that chronic inflammation induces somal hypertrophy and increases the excitability of C-fiber bladder afferent neurons by suppressing IA channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.

4-Aminopyridine↗

[Quantification of bladder tumor antigen (BTA trak) and its correlation with bladder cancer grade and stage].

OBJECTIVE: To analyze the efficacy of the BTA Trak test as a diagnostic marker for bladder cancer, determine its correlation with tumor grade and stage, compare its sensitivity with urinary cytology and its utility in urological conditions other than bladder cancer. METHODS: 77 patients comprised the study; 33 with bladder cancer and 44 without. A urine sample was obtained from all patients for the BTA Trak test and another three samples for urinary cytology from each of the 33 patients with bladder cancer. Of the 44 patients without bladder cancer, 36 had conditions involving the urinary tract and 8 presented conditions without urothelial involvement. The BTA Trak test was repeated three months after treatment in 11 of the patients with bladder cancer and three months after the first test in 13 patients without bladder cancer. RESULTS: Using BTA Trak threshold values of 14 U/ml as first reference and 50 U/ml as the value indicating clinical warning, these were found to be higher in 24 of 33 patients with bladder tumor (sensitivity 72.7%). By tumor stage, BTA Trak was positive in 12 of 21 pT1 (sensitivity 57%) and in 11 of 11 pT2 (sensitivity 100%). Concerning tumor grade, values were higher than threshold in 13 of 22 GI-II (sensitivity 59.9%) and 10 of 10 GIII (sensitivity 100%). Urinary cytology was positive in only 8 cases (sensitivity 24.4%). In the patients without bladder cancer, values are higher than threshold in 3 of 8 patients with urological conditions without urinary tract involvement and 14 of 36 with a probable urothelial involvement without tumor, accounting for an overall sensitivity of BTA Trak of 61.4%. The BTA Trak test three months after treatment showed lower value in 7 of 8 patients with bladder tumor and pretreatment values higher than threshold. CONCLUSIONS: The BTA Trak test is a simple quantitative method with a high sensitivity for the diagnosis of bladder tumors, especially those in the advanced stages and grades. It is superior to cytology, although it has a lower specificity, particularly in conditions with urinary tract involvement.

Aged↗

Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction.

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.

Adenosine Triphosphate↗

Alterations in cholinergic and neuropeptide innervation of urinary bladder following partial bladder outlet obstruction.

Posterior urethral valves (PUV) are the most common cause of bladder outlet obstruction (BOO) in infancy. Bladder instability, poor compliance and myogenic failure are responsible for the poor long-term prognosis in these patients. Previous studies have reported abundance of sensory neuropeptides, e.g. substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and acetylcholinesterase (AchE) nerves in the urinary bladder. We hypothesized that the functional changes in the bladder following BOO are due to alteration in cholinergic and sensory neuropeptide innervation. We therefore investigated cholinergic and sensory innervation of urinary bladder following BOO. Fifteen immature male guinea pigs (Hartley strain) 3-4 weeks old and weighing approximately 250 g. underwent placement of a silk ligature around the bladder neck to induce BOO. Controls included 5 sham-operated animals. The animals were killed 1, 2 and 4 weeks following obstruction, respectively. Whole-mount preparation and conventional sections of bladder wall were performed. AchE histochemistry, and single-label immunofluorescence histochemistry for SP, CGRP and VIP were utilized. Light microscopy and laser scanning confocal microscopy were used to assess the results. AchE staining showed marked increase in cholinergic innervation density within the suburothelial region following BOO. The staining for SP, CGRP and VIP demonstrated marked reduction in sensory nerve density within the suburothelial region 1 week following BOO and the lack of sensory innervation 4 weeks after BOO. The marked reduction in sensory innervation of the bladder and simultaneous increase in cholinergic innervation following BOO may lead to bladder instability and decrease in bladder compliance.

Animals↗

Parabrachial nucleus influences the control of normal urinary bladder function and the response to bladder irritation in rats.

The contribution of the parabrachial nucleus to the mediation of bladder contraction was examined in the rat. Constant infusion (0.1 ml/min) of saline or 0.2% acetic acid evoked normal or abnormal bladder contractions, respectively. Single unit activity was recorded in the parabrachial nucleus with tungsten microelectrodes. Seven units with activity that was correlated with bladder contraction during saline infusion were located in the lateral subnuclei and three units were located in the medial subnuclei of the parabrachial nucleus. Twelve units with activity that was correlated with abnormal bladder contractions were found widely distributed in the parabrachial nucleus. An inverse correlation of activity to normal or abnormal bladder contractions was identified in 11 units in the parabrachial nucleus. Pressure injection of 5 mM CoCl(2) into the parabrachial nucleus was used to block synaptic transmission unilaterally. Normal bladder contractions evoked by saline infusion were disrupted by 5 of 10 injections, 4 of them in the medial subnuclei of the parabrachial nucleus and one in the lateral subnuclei. Abnormal bladder contractions were converted to a normal pattern in nine experiments where CoCl(2) injections lay in the lateral subnuclei of the parabrachial nucleus. In five experiments, CoCl(2) disrupted abnormal bladder contractions; four effective sites were located in the lateral subnucleus and one lay in the medial subnucleus of the parabrachial nucleus. These data demonstrated that single units responding to both normal and abnormal contractions were located throughout the parabrachial nuclei whereas the lateral subnuclei play a predominant role in mediation of abnormal bladder contractions and the medial subnuclei play a predominant role in the mediation of normal bladder contractions.

Action Potentials↗

Activity and expression of nitric oxide synthase in the hypertrophied rat bladder and the effect of nitric oxide on bladder smooth muscle growth.

PURPOSE: We investigated the expression and activity of nitric oxide synthase (NOS) and the localization of cyclic guanosine monophosphate (cGMP) in hypertrophied rat bladder. We also examined whether nitric oxide (NO) has a growth inhibitory effect in bladder smooth muscle cells. MATERIALS AND METHODS: The urethra was partly ligated and the bladder was removed 3 days, 3 or 6 weeks after obstruction. NOS activity was determined as the conversion of L-[14C]citrulline from L-[14C]arginine (Amersham Life Science, Solna, Sweden). Neuronal NOS (nNOS) expression was studied with Western blot analysis and immunohistochemistry. The expression of inducible NOS (iNOS) and cGMP was evaluated by immunohistochemistry. The effect of NO on isolated bladder smooth muscle cell growth was assessed as protein and DNA synthesis by [3H]-leucine and [3H]-thymidine (NEN Life Science Products, Zaventem, Belgium) incorporation, respectively. RESULTS: Ca independent iNOS activity increased after short-term obstruction. Immunohistochemical studies in obstructed bladders demonstrated iNOS expression primarily in urothelial and inflammatory cells. Ca dependent nNOS activity decreased after obstruction, as confirmed by Western blot analysis. The cGMP immunoreactive cells were mainly found within the serosal layer of obstructed bladders. The NO donor DETA-NONOate (Alexis Biochemicals, Lausen, Switzerland) (300 microM.) reduced [3H]-leucine and [ H]-thymidine incorporation by a mean of 29% +/- 2% and 95% +/- 2%, respectively, in cultured bladder smooth muscle cells. CONCLUSIONS: Bladder obstruction caused a small increase in iNOS activity and a decrease in nNOS activity. NO was found to have a growth inhibitory effect in bladder smooth muscle cells, suggesting that changes in NOS activity may influence the progress of bladder hypertrophy.

Animals↗

Inhibition of implantation of murine bladder tumor by thiotepa in cauterized bladder.

This study was designed to determine the role of immediate intravesical instillation of single dose thiotepa post transurethral resection of bladder tumor in the prevention of recurrence by tumor implantation, using murine bladder tumor line 2 and 201 C3H/He mice. Previous studies have suggested implantation may take place as early as the first hour and reach its maximum in 24 hours after resection of bladder tumor. An in vitro dose response curve of MBT2 to thiotepa was established by treatment with various concentrations of thiotepa of 0.00, 0.01, 0.21, 0.44, and 1.91 mg./ml. In a group of 201 mice, the bladder was catheterized with a 24G angiocatheter, and a fine copper wire was inserted through the lumen. The bladder was cauterized by touching the wire with a Bovie coagulator for four seconds at the lowest setting. All bladders were instilled with 1 x 10(6) cells of murine bladder tumor line 2, followed by instillation of 1.91 mg./ml. of thiotepa with various time delays per treatment group. The bladder implantation rates were 30.4% (17/56), 3.4% (2/59), 6.5% (2/31) and 26.9% (7/26) in the control, immediate, one-hour delay and 24-hour delay groups, respectively. The urethral implantation rates were 21.4% (12/56), 0% (0/59), 6.5% (2/31) and 0% (2/26), respectively. The overall implantation rates (bladder, urethra, or both) were 42.9% (24/56), 3.4% (2/59), 6.5% (2/31) and 25.9% (7/27), respectively. Implantation rates were significantly higher in the control and 24-hour delay groups than in the immediate and one-hour instillation groups (p less than 0.05, Fisher Exact Test). We conclude from this animal model that intravesical instillation of single dose thiotepa, to be effective, should be initiated within the first hour after tumor resection, since it dramatically decreased the incidence of bladder and urethral implantation.

Administration, Intravesical↗

Ureteral reimplantation before bladder neck plasty in the reconstruction of bladder exstrophy: indications and outcomes.

OBJECTIVES: After initial closure, all exstrophy patients have vesicoureteral reflux. This reflux is usually managed with antimicrobial prophylaxis, surveillance, and ureteral reimplantation concurrent with bladder neck plasty. Patients with recurrent urinary tract infections or worsening hydronephrosis may require earlier correction of reflux. This subset of patients was reviewed to determine the ability to correct reflux adequately, the difficulty with subsequent bladder neck plasty, and the long-term continence results. METHODS: We reviewed an exstrophy database of more than 700 patients and identified 19 who underwent ureteral reimplantation independent of bladder neck plasty. All had undergone bladder closure in infancy. Eleven had since undergone modified Young-Dees-Leadbetter bladder neck plasty. Five patients were awaiting bladder neck reconstruction, 2 girls were continent without bladder neck plasty, and one had undergone augmentation. RESULTS: Indications for early ureteral reimplant were recurrent febrile infections despite adequate prophylaxis (n = 15) or worsening hydronephrosis on follow-up (n = 4). In the 11 patients who had undergone subsequent bladder neck repair, prior reimplantation did not increase the operative difficulty or complications. The continence results among these 11 were comparable with those in patients without prior reimplantation. In 1 patient, reflux recurred and was corrected at the time of bladder neck plasty. None had further urinary tract infections, and hydronephrosis improved in three and stabilized in one. CONCLUSIONS: In patients who present with recurrent infections or worsening hydronephrosis after initial exstrophy closure, early reimplantation can be undertaken. If performed with later bladder neck plasty in mind, the surgical treatment of incontinence is not compromised and recurrent infections and upper tract changes will be abated.

Abdominal Wall↗