Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia.

PURPOSE: Detrusor overactivity contributes to bothersome constellation of lower urinary tract symptoms (LUTS) in men and women as they age. However, the underlying mechanisms of non-obstructive detrusor overactivity and LUTS remain largely unknown. Growing evidence suggests that ischemia may be an independent factor in the development of non-obstructive bladder dysfunction. Our goal was to determine the effects of ischemia on detrusor function and voiding behavior and define redox-mediated cellular stress and cell survival signaling in the ischemic bladder. MATERIALS AND METHODS: Male Sprague Dawley rats were randomly divided into treatment (n=8) and control (n=8) groups. In the treatment group, iliac artery atherosclerosis and chronic bladder ischemia were induced. At 8 weeks after bladder ischemia, voiding patterns were examined in metabolic cages, cystometrograms were recorded in conscious animals, and then bladder blood flow was measured under general anesthesia. Bladder tissues were processed for assessment of transcription factors, markers of cellular and mitochondrial stress, mitochondrial respiration, and cell survival signaling pathway. RESULTS: Atherosclerotic occlusive disease spread from the common iliac arteries to the internal iliac and vesical arteries and produced sustained bladder ischemia. Studies in metabolic cages showed increased micturition frequency and decreased voided volume in bladder ischemia. Conscious cystometrograms produced consistent data showing significant increase in micturition frequency and decreased voided volume and bladder capacity. Voiding behavior and cystometric changes in bladder ischemia were associated with significant decrease in DNA binding activity of Nrf2, significant increase in cellular levels of stress protein Hsp70 and mitochondrial stress protein GRP75, and significant decrease in mitochondrial oxygen consumption and upregulation of PI3K and Akt expression. CONCLUSION: Chronic bladder ischemia may be a mediating variable in the development of detrusor overactivity in the non-obstructive bladder. The mechanism may involve ischemia-induced cellular stress, Nrf2 functional deficit, depression of mitochondrial respiration, and upregulation of PI3K/Akt cell survival signaling pathway.

Regional distribution and molecular interaction of caveolins in bladder smooth muscle.

UNLABELLED: What's known on the subject? and What does the study add? Caveolae are specialised regions of bladder smooth muscle (BSM) cell membranes where specific signalling pathways are regulated. Caveolin proteins are involved in caveolar biogenesis and function as signal transduction regulators. Expression of caveolin-1, -2, and -3 has been previously identified in the bladder; however, the distribution and relative expression of these proteins have not been defined. The present data show significant differences in the spatial distribution of caveolin proteins throughout the bladder wall. Region dependent variations in the co-localisation of caveolin subtypes in detrusor SM were also detected. These findings support the premise that the unique spatial pattern of caveolin proteins associated with BSM cells may enable regionally distinct functional responses to common stimuli. OBJECTIVE: • To determine the regional expression profile of caveolin isoforms (integral membrane proteins abundant in caveolae), the spatial relationships among caveolin proteins within specific smooth muscle (SM) regions and the extent of their molecular interactions in bladder SM (BSM). MATERIALS AND METHODS: • Regional differences in the expression of caveolin family members were determined by quantitative reverse transcriptase-polymerase chain reaction and Western blot of RNA and protein extracted from the base, body and dome of rat bladders. • To evaluate the distribution of caveolin-1 (Cav-1), Cav-2 and Cav-3 within the bladder, longitudinal tissue sections from the base to dome were processed for confocal microscopy and quantified for intensity of immunoreactivity (IR) and extent of co-localisation. • Interactions among Cav-1, Cav-2 and Cav-3 were determined by co-immunoprecipitation. RESULTS: • Differential expression of Cav-1 and Cav-3 was detected among bladder regions, with lowest expression in the bladder base relative to the dome. • Cav-1 was highly expressed in all regions, although an increase in IR from submucosa to serosa was detected in each region. • The distribution of Cav-2 IR generally paralleled Cav-1, but progressively decreased from submucosa to serosa in each region. • Cav-3 expression predominated in the medial region of BSM increasing progressively from base to dome, but was poorly expressed in the outer SM layer particularly in the dome. • Cav-1 co-precipitated extensively with both Cav-2 and Cav-3. Co-precipitation between Cav-3 and Cav-2 was also detected. CONCLUSIONS: • The isoform-specific spatial distribution and distinct molecular interactions among caveolins in BSM may contribute to the contractile heterogeneity of BSM cells and facilitate differential modulation of responses to local stimuli. • As BSM caveolae regulate key signalling processes involved in contraction, altered expression of caveolin proteins may generate a regional imbalance in contraction/relaxation responses, thus leading to bladder dysfunction.

Altered caveolar mediated purinergic signaling in spontaneously hypertensive rats with detrusor overactivity.

PURPOSE: Loss of bladder smooth muscle caveolae, which are membrane invaginations involved in signaling regulation, is associated with detrusor dysfunction. We investigated whether caveolar loss in bladder smooth muscle from SHR rats contributes to detrusor overactivity by dysregulating caveolar mediated signaling. MATERIALS AND METHODS: Caveolar density and caveolin-1 protein expression were compared between SHR and WKY rats by ultrastructural and molecular analysis. The functional effects of caveolar depletion achieved by methyl-ß-cyclodextrin on neurogenic and agonist induced contractions, and spontaneous activity in isolated bladder tissue were also compared between the strains. P2X1 receptor and caveolin-1 interaction was investigated by confocal microscopy, co-immunoprecipitation and proximity ligation assay. RESULTS: Bladder smooth muscle caveolar density and caveolin-1 expression were decreased in SHR vs WKY rats. Responses to α-ß-methylene adenosine triphosphate at baseline were lower in SHR than in WKY rats. Methyl-ß-cyclodextrin significantly decreased α-ß-methylene adenosine triphosphate responses in WKY rats but had less effect in SHR rats. Methyl-ß-cyclodextrin decreased the amplitude of the purinergic component of neurally mediated contractions in each strain but had no effect on the cholinergic component. Bladder spontaneous activity was significantly higher in SHR than in WKY rats. Exposure to methyl-ß-cyclodextrin or P2X1 receptor antagonist significantly increased spontaneous activity in WKY rats but had no effect in SHR rats. P2X1 receptor and caveolin-1 were co-localized and co-precipitated in bladder smooth muscle tissue. CONCLUSIONS: Caveolar depletion in WKY bladders results in a functional phenotype analogous to that of overactive SHR bladder. The intrinsically decreased caveolae in SHR rats causes loss of the caveolar mediated regulation of purinergic signaling and augmented spontaneous activity, conditions that may lead to detrusor overactivity.

Loss of bladder smooth muscle caveolae in the aging bladder.

AIMS: Caveolae are specialized regions of the cell membrane that modulate signal transduction and alterations in these structures affect bladder smooth muscle (BSM) contraction. Since bladder dysfunctions are common in the elderly, we evaluated the effect of aging on the morphology of caveolae and caveolin protein expression in BSM. METHODS: Caveolar morphology (number, size, and depth) in BSM was determined from electron microscopy images of young (10 weeks), adult (6-month old), and old (12-month old) rat urinary bladders. Changes in expression levels of caveolin proteins with age were investigated by Western blot and immunofluorescence microscopy. Caveolin-3 gene expression was determined by real-time RT-PCR in young and 19-month-old rat bladders. RESULTS: Twelve-month-old animals exhibited 50% fewer BSM caveolae compared to young (P < 0.01). The area of caveolae was significantly decreased at 6 and 12 months. Despite a decrease in the number of BSM caveolae at 12 months, the expression of caveolin-1 and cavin-1 were unaltered with age. In contrast, caveolin-2 and caveolin-3 protein expression and immunoreactivity were reduced in BSM at 6 and 12 months of age. Caveolin-3 gene expression was also downregulated at 19 months compared to young animals. CONCLUSION: Biological aging significantly decreases BSM caveolae number and morphology with associated selective alteration in caveolin protein expression. Since caveolae are protected membrane regions that regulate signal transduction, age-related alterations in caveolae and caveolin protein expression could alter BSM contractility resulting in bladder dysfunctions of the elderly.

Spectrum of urodynamic abnormalities and renal function changes in adult men with non-neurogenic urinary retention.

INTRODUCTION: The purpose of this study was to identify abnormalities in bladder and renal function in men with urinary retention presumed to be due to BPH. METHODS: In this retrospective analysis, urodynamic studies (UDS) and renal function were evaluated. Bladder contractility and compliance and the severity of bladder outlet obstruction (BOO) were determined from urodynamics. Renal function (BUN, creatine, eGFR) was assessed prior to retention, at the time of presentation and after urodynamic evaluation. RESULTS: Of 87 patients with evaluable UDS, 48% did not demonstrate detrusor activity during testing while 52% showed some detrusor contractile activity. Of these, 23% did not have BOO. Diminished bladder compliance was detected in 56%. In the entire cohort, BUN, serum creatinine, and eGFR were significantly changed during retention but were restored after catheterization. In older patients (>75 years), BUN and creatinine during retention were significantly higher, and eGFR was significantly lower compared to younger patients, but renal function after catheterization was not different between age groups. No significant correlations were found between renal function measurements and bladder compliance or age. CONCLUSION: The urodynamic spectrum in men with urinary retention ranged from detrusor acontractility to varied degrees of contractility associated with outlet obstruction spanning from equivocal to severe. Moreover, prompt relief of retention restores renal function to baseline levels, regardless of age. This study indicates that prostatic obstruction may not be the only cause of urinary retention in adult men presumed to have BPH and illustrates the value of urodynamic assessment prior to potentially failure-prone surgical interventions.

Human bladder smooth muscle cell damage in disturbed oxygen tension.

OBJECTIVE: To characterize human bladder smooth muscle cell reactions to disturbed oxygen tension. Clinical studies have shown a close correlation between bladder ischemia and lower urinary tract symptoms in elderly patients. MATERIALS AND METHODS: Confluent cultured human bladder smooth muscle cells were incubated under normoxia, continuous hypoxia, and oxidative stress (hypoxia/reoxygenation) conditions using a computerized oxycycler system. After 48 hours, cell samples were collected and processed for fluorometric assessment of oxidative injury, enzyme immunoassay of antioxidant capacity, and transmission electron microscopy. RESULTS: Lipid peroxidation was found in cell hypoxia and oxidative stress, whereas protein oxidation was evident in oxidative stress only. Cell antioxidant capacity decreased in oxidative stress but remained unchanged in hypoxia. Oxidative products were present in cell oxidative stress only, whereas nitrosative products increased in both hypoxia and oxidative stress conditions. Forty-eight hours of hypoxia and oxidative stress had no effect on cell senescence. Thickened deformed cell membrane, swollen mitochondria, and enlarged endoplasmic reticulum (ER) were found in cell hypoxia. Partially lost cell membrane with increased caveolae, swollen mitochondria with degraded cristae, splintered ER, and increased lysosomes were evident in cell oxidative stress. CONCLUSION: Human bladder smooth muscle cells are highly reactive to nonconforming oxygen tension. Reactions to hypoxia are consistent with cell survival signaling to cope with lack of oxygen. Changes in oxidative stress indicate extensive damage and deterioration of the subcellular elements. Hypoxic and oxidative damage may be an important mechanism of smooth muscle degeneration in bladder conditions with disturbed oxygen tension.

Oxidative modification of mitochondrial integrity and nerve fiber density in the ischemic overactive bladder.

PURPOSE: To our knowledge the mechanism of neurodegeneration in the overactive bladder remains unknown. We examined mitochondrial integrity and searched for markers of oxidative neural injury in the ischemic overactive bladder. MATERIALS AND METHODS: A rabbit model of overactive bladder was developed by inducing moderate pelvic ischemia. After 16 weeks cystometrograms and blood flow recordings from overactive bladders were compared with those in age matched controls. Bladder tissues were processed to assess oxidative products, oxidative stress sensitive genes and nerve fiber density using enzyme immunoassay, quantitative real-time polymerase chain reaction and immunohistochemical staining, respectively. Tissue ultrastructure was examined by transmission electron microscopy. RESULTS: Ischemia increased spontaneous bladder contractions and led to cyclic ischemia-reperfusion. Tissue levels of oxidative and nitrosative products, and oxidative stress sensitive genes encoding superoxide dismutase and aldose reductase were up-regulated in the overactive bladder. Transmission electron microscopy of overactive bladder tissues showed mitochondria with distinctive morphological features, characterized by swollen membranes, decreased granules, a total loss of granules and sporadic membrane damage. These changes were associated with sporadic loss of epithelial mucosal membrane, twisted smooth muscle cells, diffused vacuolization and marked neurodegeneration. CONCLUSIONS: Our findings suggest free radical mediated ultrastructural damage and neurodegeneration in the overactive bladder. Overactivity associated mitochondrial stress may have a central role in epithelial damage, smooth muscle cell injury and neurodegeneration. Superoxide dismutase and aldose reductase up-regulation in the overactive bladder imply intrinsic defensive reaction against free radicals that apparently fails to prevent oxidative damage and neurodegeneration. Therapeutic strategies targeting basic mitochondrial processes such as energy metabolism or free radical generation may help better manage wall degeneration and neuropathy in the overactive bladder.

Oxidative stress and neurodegeneration in penile ischaemia.

OBJECTIVE: To seek markers of oxidative stress and examine neural structural integrity in chronic penile ischaemia using a rabbit model of arteriogenic erectile dysfunction (ED), as the role of ischaemia in penile neuropathy and the oxidative mechanism of neurodegeneration in ED remains unknown. MATERIALS AND METHODS: A rabbit model of atherosclerosis-induced ED was developed by partial balloon de-endothelialization of the iliac arteries. After 10 weeks, intracavernosal blood flow and erectile function in the arteriogenic ED group were compared with age-matched controls. Erectile tissues were processed for analysis of oxidative stress markers and nerve fibre density using enzyme immunoassay and immunohistochemical staining, respectively. Oxidative stress-sensitive genes were determined with quantitative real-time polymerase chain reaction. Tissue ultrastructure was examined by transmission electron microscopy. RESULTS: Significant erectile tissue ischaemia, erectile dysfunction, increased levels of oxidative products, and marked nitrotyrosine immunoreactivity was evident in the ED group. Oxidative stress-sensitive genes encoding hypoxia inducible factor-1alpha (HIF-1alpha), superoxide dismutase (SOD), aldose reductase (AR) and nerve growth factor (NGF) were up-regulated in the ischaemic erectile tissue. These changes were associated with collapsed axonal and Schwann cell profiles, neurodegeneration, mitochondrial structural damage, increased caveolae, loss of endothelium, and sporadic vacuolization. CONCLUSIONS: Neuropathy appears to follow the vascular insult in arteriogenic ED. Neural injury in penile ischaemia involves a neurovascular phenomenon mediated by oxidative free radicals. Mitochondrial structural damage and increased HIF-1alpha gene expression may be early signals of oxidative stress and neurodegeneration in ED. Up-regulation of SOD, AR and NGF may be a coordinated defensive reaction to oxidative radicals that seems to fail to prevent neural injury in the ischaemic penis. Our study introduces the concept of oxidative neurodegeneration in the pathophysiology of arteriogenic ED. Therapeutic strategies to protect penile nerves from free radical incursion may enhance the efficacy of surgical and pharmacological interventions in arteriogenic ED.

Oxidative stress and neurodegeneration in the ischemic overactive bladder.

PURPOSE: The central and peripheral nervous systems are highly sensitive to ischemia and oxidative stress. We searched for markers of oxidative injury and examined neural density in the rabbit ischemic overactive bladder. MATERIALS AND METHODS: Blood flow and oxygenation were recorded during cystometrogram in overactive and control rabbit bladders at weeks 8 and 16 after the induction of ischemia. Oxidative products and neural density were assessed by enzyme immunoassay and immunohistochemical staining, respectively. Reverse transcriptase-polymerase chain reaction was done to determine the gene expression of nerve growth factor and its receptor p75. The effect of acute oxidative stress was examined in tissue culture medium containing H(2)O(2). RESULTS: Overactivity produced repeating cycles of ischemia/reperfusion and hypoxia/reoxygenation in the ischemic bladder, leading to oxidative and nitrosative products. Neural density in the 8-week ischemic bladder was similar to that in controls, while neurodegeneration was evident after 16 weeks of ischemia. Nerve growth factor gene levels initially increased at week 8 but significantly decreased at week 16 after the induction of ischemia. Gene levels of p75 decreased after 8 weeks and remained lower than in controls after 16 weeks of ischemia. Acute oxidative stress decreased nerve growth factor protein release in culture medium. The antioxidant enzyme catalase had no significant effect on control tissues but it partially protected nerve growth factor from H(2)O(2) injury. CONCLUSIONS: Ischemia may have a role in bladder neuropathy. Overactivity under ischemic conditions produces noxious oxidative products in the bladder. Neurodegeneration in bladder ischemia may involve a lack of nutrients, hypoxia and overactivity induced free radicals. Nerve growth factor and its receptors may regulate neural reactions to oxidative injury.

Effect of urethral compliance on the steady state p-Q relationships assessed with a mechanical analog of the male lower urinary tract.

AIMS: Using a lumped parameter theoretical model of bladder outlet function, we previously explored the relationship between the tube law of the urethra and the pressure-flow characteristics during micturition [Mijailovich et al., 2004]. To validate this theoretical model, we constructed a mechanical analog of the male lower urinary tract that incorporated elements simulating all relevant parameters of the theoretical model. In addition, we determined the effect of alterations in compliance of the flow-controlling zone on these relationships. METHODS: In the mechanical analog, the bladder neck and urethra were represented by a thin-walled conduit made of latex rubber and the prostate with a fluid filled cuff of variable compliance encircling the conduit. We measured in the same system steady-state pressure-flow (p-Q) and pressure-area (p-A) relationships of the flow-controlling zone. The effects of bladder outlet obstruction and prostatic compliance on these relationships were simulated by varying cuff pressure and capacitative coupling of the cuff, respectively. RESULTS: We demonstrated two previously described flow regimes-critical for low Q, and subcritical for higher Q. In the critical flow regime, the cross-sectional area of the collapsible conduit downstream of the cuff became narrow up to a site where the area suddenly expanded (elastic jump). Pressure losses across the cuff region decreased with increasing Q as the elastic jump approached the cuff, and the jump vanished when Q became subcritical. By altering prostatic cuff compliance and cuff pressure, we showed that an increase in opening pressures was associated with a steeper p-Q relationship. CONCLUSIONS: Using this mechanical analog, the measurements of p-A and p-Q relationships under various experimental conduit conditions validated our previous theoretical model of the male lower urinary tract. Both the experimental measurements and our previous theoretical model predictions indicate that an increase in opening pressure is associated with an increase in the slope of the p-Q relationship which becomes steeper with decreased cuff compliance. These data are in accordance with urodynamic findings in patients with benign prostatic hypertrophy (BPH) and suggest that a reduction in prostatic compliance exacerbates the severity of obstruction.

Theoretical analysis of the effects of viscous losses and abdominal straining on urinary outlet function.

AIMS: The aim of this study was to theoretically explore the relationship between the tube law (TL) of the urethra and the pressure-flow (p-Q) relationship during micturition. The understanding of this relation is important for the evaluation of outlet obstruction by urodynamic interpretation of p-Q plots. METHODS: We simulated the outlet function by a lumped theoretical model, and suggested how the TL can be used to quantitatively predict the p-Q relationship of the system. Our analysis considered the relation between the TL and the steady state p-Q plot for various TLs including the hysteresis of the pressure-area relationship. RESULTS AND CONCLUSIONS: The inclusion of pressure losses distal to the flow controlling zone and experimentally measured p-A relations of the urethra in the model lead to the predictions that flow in the flow controlling zone is not always critical but is often in the sub-critical range, that an increase in abdominal pressure can increase the flow under certain conditions, and that hysteresis in the pressure-area relation is correlated to the hysteresis in the p-Q plot.

Correlation among maximal urethral closure pressure, retrograde leak point pressure, and abdominal leak point pressure in men with postprostatectomy stress incontinence.

OBJECTIVES: To assess the correlation among abdominal leak point pressure (ALPP), maximal urethral closure pressure (MUCP), and retrograde leak point pressure (RLPP) in the evaluation of men with stress urinary incontinence (SUI) after radical prostatectomy. METHODS: Patients were evaluated with a self-administered questionnaire regarding pad use and with multichannel videourodynamics. The ALPP, MUCP, and RLPP were compared with each other and with the severity of SUI. RESULTS: The mean ALPP was 49.4 +/- 24.4 cm H(2)O. The mean MUCP was 52.0 +/- 21.1 cm H(2)O. The mean RLPP was 48.0 +/- 13.5 cm H(2)O. No statistically significant difference in the mean values of the three parameters was found. Regression analysis revealed a statistically significant correlation among the three parameters: RLPP versus MUCP, r = 0.59, P <0.005; MUCP versus ALPP, r = 0.75, P <0.0001; and RLPP versus ALPP, r = 0.79, P <0.0001. ALPP, MUCP, and RLPP were each significantly related to pad use. CONCLUSIONS: Intrinsic sphincter deficiency is the primary cause of SUI after radical prostatectomy. Therefore, evaluation of intrinsic sphincter function is important in the treatment of postprostatectomy SUI. In incontinent men after radical prostatectomy, with a dysfunctional bladder neck and proximal sphincter unit, the intrinsic function of this distal sphincter may be assessed equally well by evaluating the resistance to antegrade leakage, retrograde leakage, or profilometric measurement of the urethral closure pressure. RLPP and MUCP offer reliable alternatives to ALPP for the evaluation of postprostatectomy SUI.

Ureteral function is modulated by a local renin-angiotensin system.

PURPOSE: Although many aspects of ureteral physiology are well characterized, the exact mechanism of ureteral smooth muscle modulation has not been fully established. In other smooth muscle contractility is modulated by angiotensin II (AngII). We determined the presence of a local ureteral renin-angiotensin system and characterized the functional role of AngII in ureteral smooth muscle. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction was performed to determine the expression of angiotensinogen, renin, angiotensin-converting enzyme and angiotensin receptor subtype 1 mRNA. The presence of AngII in ureteral tissue was determined by immunohistochemistry. Human and pig ureteral smooth muscle strips were suspended in tissue baths to determine the effect of the AngII receptor antagonist losartan on the frequency and amplitude of spontaneous ureteral contractions. Electrical field stimulation was performed before and after exposure to losartan. RESULTS: Angiotensinogen, renin, angiotensin-converting enzyme and angiotensin receptor subtype 1 mRNA expression was detected in human ureter. Immunoreactivity for AngII was demonstrated in smooth muscle bundles and blood vessels of the ureter. Losartan decreased the amplitude and frequency of spontaneous ureteral contractions as well as the contractile response to electrical field stimulation in a dose dependent manner. CONCLUSIONS: Gene expression of AngII precursors and receptor, and localization of AngII in the ureter suggest the presence of a local renin-angiotensin system in the ureter. The effect of AngII receptor antagonist on contractile responses suggests that AngII modulates ureteral smooth muscle contractile function. Therefore, a local renin-angiotensin system may have an important role in ureteral function under physiological and pathological conditions.

Structural basis of neurogenic bladder dysfunction. II. Myogenic basis of detrusor hyperreflexia.

PURPOSE: We describe the ultrastructure of detrusor smooth muscle in long-standing neurogenic bladder dysfunction in the human. MATERIALS AND METHODS: Detrusor biopsies were obtained from (15 female and 31 male) patients 7 to 96 years old with neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 spinal cord injury and 12 brain disorder. Urodynamically, all patients had detrusor hyperreflexia (neurogenic detrusor overactivity) in addition to bladder outlet obstruction in 4, impaired detrusor contractility in 19, decreased bladder compliance in 4, and detrusor-sphincter dyssynergia in 24. Ultrastructural changes in detrusor, including those associated with detrusor overactivity, impaired detrusor contractility and bladder outlet obstruction, were evaluated qualitatively and quantitatively. RESULTS: Intermediate junctions of muscle cells were absent or reduced in 45 biopsies, which instead had dominant intimate cell appositions with much narrower junctional gaps. A greater than 2 intimate cell apposition-to-intermediate junction ratio was present in 45 biopsies (98%), and intimate cell apposition linked chains of 5 muscle cells or greater in all biopsies (100%). Muscle cell degeneration was observed in 34 biopsies from 20 of 27 patients (74%) with normal contractility and 14 of 19 (74%) with impaired detrusor contractility. No particular changes were associated with functional bladder outlet obstruction due to detrusor-sphincter dyssynergia. CONCLUSIONS: The ultrastructural complete dysjunction pattern is a feature of hyperreflexia as well as nonneuropathic detrusor overactivity of various etiology. A greater than 2 intimate cell apposition-to-intermediate junction ratio had 98% sensitivity but its specificity remains to be determined. The lack of relationship between muscle cell degeneration and detrusor contractility probably reflects limitations of urodynamic measurement of contractility in patients with spinal cord injury and meningomyelocele.

Structural basis of neurogenic bladder dysfunction. I. Methods of prospective ultrastructural study and overview of the findings.

PURPOSE: We standardize procedures for ultrastructural study of detrusor smooth muscle and intrinsic nerves in neurogenic bladder dysfunction in the human, and present an overview of the findings. MATERIALS AND METHODS: The study included 18 female and 33 male patients 7 to 96 years old. They had neurogenic bladder dysfunction with hyperreflexia for less than 1 to 43 years, resulting from upper motoneuron lesions (spinal cord injury 25, brain disorder 17) or combined upper and lower motoneuron deficit (meningomyelocele 9). Endoscopic or open bladder biopsies were processed for ultrastructural study of detrusor smooth muscle and intrinsic neural elements. Qualitative morphologic criteria of muscle cell arrangement, degeneration and cell-cell contacts, as well as those of degeneration and regeneration of intrinsic neural elements are defined. RESULTS: Five biopsies from the brain disorder group had insufficient smooth muscle and were excluded from study. The remaining 46 biopsies were evaluated by electron microscopy, and all displayed the complete dysjunction pattern of detrusor overactivity. Most displayed degeneration and regeneration of intrinsic axons but disproportionately limited muscle cell degeneration, irrespective of detrusor contractility. The brain disorder group biopsies displayed many more ultrastructurally normal axons than the meningomyelocele and spinal cord injury group biopsies (median 33% versus 8% or less). CONCLUSIONS: Upper motoneuron neurogenic bladder dysfunction in humans is associated with intrinsic neuromuscular defects in the detrusor. Ultrastructural features of these defects suggest morphologic markers that not only may distinguish neuropathic from nonneuropathic bladder dysfunction, but also may point to the anatomical level of the neurogenic deficit.

Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation.

PURPOSE: We studied the ultrastructure of intrinsic detrusor innervation in long-standing neurogenic bladder dysfunction in the human. MATERIALS AND METHODS: Endoscopic or open detrusor biopsies were obtained from 15 female and 31 male patients 7 to 96 years old who had hyperreflexic neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 had spinal cord injury and 12 had a brain disorder. Changes in intrinsic detrusor nerves were evaluated by electron microscopy qualitatively and quantitatively according to predefined criteria. RESULTS: Axonal degeneration was observed in 44 of the 45 biopsies with discernible intrinsic nerves. Structurally normal axons were 5(1/2) or 4 times more common in brain disorder than meningomyelocele or spinal cord injury group biopsies (median 33%, 6%, 8%, respectively). Axonal regeneration, not encountered in nonneuropathic dysfunctional detrusors, was observed in restricted distribution in most biopsies (76%) and was independent of the duration of neurogenic bladder dysfunction. Axon sprouts were observed in 17 biopsies (38%), and copeptidergic axons formed 20% (median per biopsy) of discernible axon profiles in contrast to less than 1% in normal detrusor. Activated Schwann cells were observed in all but 1 biopsy. The axonal changes were not associated with the level or degree of spinal cord lesion in patients with meningomyelocele or spinal cord injury. CONCLUSIONS: Combined degeneration and regeneration is the characteristic change in intrinsic nerves of detrusor in upper motoneuron neurogenic bladder dysfunction. The observed changes offer the possibility of clinically recognizing neuropathic contribution to a dysfunctional detrusor, as well as the potential to distinguish its spinal versus supraspinal etiology.

Bladder cancer in patients with spinal cord injury.

OBJECTIVE: The incidence of bladder cancer in spinal cord injury (SCI) is 16 to 28 times higher than that in the general population. The objective of this study was to investigate the characteristics of bladder cancer that are unique to the SCI population. DESIGN: Retrospective review. METHODS: The charts of 16 patients diagnosed with bladder cancer from 1982 to 2001 were reviewed for type of cancer, exposure to risk factors, presenting symptoms, and survival time. RESULTS: The presenting manifestations were gross hematuria in 14 patients, papillary urethral growth in 1 patient, and acute obstructive renal failure in 1 patient. The diagnosis was made on initial cystoscopic evaluation in 16 patients; 3 patients required further evaluation. Eight of the 11 screening cytologies were suspicious for a malignancy prior to the diagnosis. Seven patients had transitional cell carcinoma, 6 patients had squamous cell carcinoma (SCCA), and 3 patients had both. The bladder wasmanaged with chronic indwelling catheter in 12 patients. Nine patients died of bladder cancer metastases and the remaining 3 patients died of other causes. Six patients survived 5 years or more; 4 were still alive at the completion of this study. CONCLUSION: Gross hematuria in individuals with SCI warrants aggressive assessment for bladder cancer. Chronic indwelling catheter, smoking, and renal and bladder stones are important risk factors for cancer. The incidence of SCCA in the SCI popullation is much higher than in the general population. Cystoscopic and cytologic evaluation in patients with advanced disease may fail to confirm the diagnosis in a high proportion of patients.