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Background: Contrasting findings have been reported regarding a possible constitutive expression of inducible nitric oxide synthase (iNOS) in a normal mammalian bladder. The current study was designed to further investigate such putative iNOS expression., Materials and Methods: The experiments were conducted with paraffin-embedded archival material from the urinary bladder of 6 normal, male Sprague-Dawley rats. In addition, two normal female mice (C57BL/6) were sacrificed and the urinary bladders were harvested. The occurrence of iNOS mRNA was examined by the RNAScope in situ hybridization method. Protein expression of iNOS and 3-nitrotyrosine (the latter used as an indicator of oxidative stress) was investigated by immunohistochemistry., Results: No expression of iNOS mRNA was observed in the bladder tissue. iNOS protein and 3-nitrotyrosine were strongly expressed in the urothelium. iNOS was also expressed perinuclearly in the detrusor., Conclusions: Although the RNAScope methodology could not demonstrate mRNA for iNOS in the normal urinary bladder, the results by immunohistochemistry strongly suggest the occurrence of iNOS in particular, in the urothelium. Positive reactivity for 3-nitrotyrosine may indicate ongoing oxidative stress of the urothelium. The finding of perinuclear iNOS immunoreactivity could suggest an intracrine signaling function by iNOS to the nucleus.

Objective: We have previously demonstrated protein expression of the extracellular matrix degrading protein ADAMTS5 in the nuclei of urothelial cells in healthy rats. The proteoglycan versican constitutes one of the main substrates for this protease. In this follow up study we investigated a potential co-localization of versican and ADAMTS5 in the urinary bladder wall. Material and Methods: The study was conducted with archive material (paraffin embedded bladder tissue from our previous study, i.e., 8 male Sprague-Dawley rats). Protein expression of versican was investigated by immunohistochemistry. Furthermore, the occurrence of versican mRNA was examined by in-situ hybridization. Results: Positive immunoreactivity for versican was evident in the urothelium but also, weakly, in the detrusor. This expression was localized only in the cytoplasm, leaving the nuclei devoid of reactivity. Interestingly, versican mRNA was only sparsely observed in the urothelial cells. Conclusions: We found by immunohistochemistry that the substrate for ADAMTS5, versican, was localized in the cytosol of urothelial cells. This demonstrates a difference regarding the expression of ADAMTS5, which was emphasized in the nuclei. This could imply an additional, non-enzymatic, function of ADAMTS5 in the urothelium.

Objective: The aim of this study was to investigate whether protein expression of the extracellular matrix-degrading protease ADAMTS5 can be demonstrated in the urinary bladder of healthy rats, and, if so, to determine the localization of this enzyme., Materials and Methods: The experiments were conducted with eight inbred male Sprague-Dawley rats. Immunohistochemistry was used to investigate the expression of ADAMTS5 in the urinary bladder. Negative controls were established by either excluding the primary antibody or applying the antibody after it had been preabsorbed with its immunogenic peptide. Confocal microscopy was used to visualize the distribution of ADAMTS5 in the urinary bladder tissue., Results: Immunoreactivity for ADAMTS5 was demonstrated in the urothelium and in the detrusor. This expression was localized not only in the cytoplasm, but also in the nuclei. Confocal microscopy corroborated these findings., Conclusion: Expression of ADAMTS5 was demonstrated in the cytoplasm as well as in the nuclei of the urothelium and detrusor cells, suggesting that it may play a role at the transcriptional level.

Purpose: Bladder wall nitric oxide production in patients with bladder pain syndrome type 3C is increased compared to undetectable nitric oxide in patients with nonHunner bladder pain syndrome and healthy controls. However, the underlying mechanism/s of the increased nitric oxide production is largely unknown. We compared mRNA expression of a select group of cytokines in patients with bladder pain syndrome/interstitial cystitis type 3C and in pain-free controls., Materials and Methods: Cold cup biopsies from 7 patients with bladder pain syndrome type 3C and 6 healthy subjects were analyzed. mRNA expression of IL-4, 6, 10 and 17A, iNOS, TNF-α, TGF-β and IFN-γ was estimated by real-time polymerase chain reaction. IL-17 protein expression was determined by immunohistochemistry. Mast cells were labeled with tryptase to evaluate cell appearance and count., Results: IL-6, 10 and 17A, and iNOS mRNA levels as well as the number of mast cells infiltrating the bladder mucosa were significantly increased in patients with bladder pain syndrome type 3C compared to healthy controls. TNF-α, TGF-β and IFN-γ mRNA levels were similar in patients and controls. IL-17A expression at the protein level was up-regulated and localized to inflammatory cells and urothelium in patients with bladder pain syndrome type 3C., Conclusions: Patients with bladder pain syndrome/interstitial cystitis had increased mRNA levels of IL-17A, 10 and 6, and iNOS. IL-17A might be important in the inflammatory process. To our knowledge the increase in IL-17A is a novel finding that may have new treatment implications., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Interstitial cystitis is regarded as a heterogenous syndrome with two distinguishable forms: the non-ulcer and the classic form of interstitial cystitis, the latter with Hunner's lesions; or bladder pain syndrome type 3C and non-Hunner bladder pain syndrome, respectively., Methods: A cohort of 379 patients diagnosed with interstitial cystitis was studied. Nitric oxide release from the bladder was measured using a chemiluminescence nitric oxide analyzer. Bladder biopsies from the patients and healthy controls were analyzed by routine histopathological examination. Biopsies from a subset of patients and controls were also analyzed by immunohistochemistry and cytokine gene expression by real-time polymerase chain reaction., Results: Patients with bladder pain syndrome type 3C/classic interstitial cystitis had considerably higher levels of nitric oxide as compared with non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients and healthy individuals, and showed histologically a chronic inflammation in the bladder mucosa, with abundant mast cell infiltration in all layers of the bladder wall. No inflammation was noted in non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients. The isoenzymes inducible nitric oxide synthase, the catalyst in the nitric oxide production, was strongly expressed in the inflammatory cells in the bladder mucosa of bladder pain syndrome type 3C/classic interstitial cystitis patients. In addition, the expression of the pro-inflammatory cytokines interleukin-6 and interleukin-17A messenger ribonucleic acid, and of anti-inflammatory interleukin-10 messenger ribonucleic acid showed significantly increased levels in bladder pain syndrome type 3C/classic interstitial cystitis compared with healthy controls., Conclusion: Bladder pain syndrome type 3C/classic interstitial cystitis is a distinct inflammatory disease and in many aspects shares features of inflammatory autoimmune diseases. These findings could open up novel research avenues with expectations for new targets for pharmacological treatment., (© 2014 The Japanese Urological Association.)

The contents and understanding of the term, interstitial cystitis, have undergone major changes during the past 100 years, moving from a chronic, true inflammatory bladder disorder to an extensive syndrome with lower urinary tract pain. Comments on this development are presented. From examples in the literature, some important features of classic interstitial cystitis are outlined. The more inclusive attitude of later decades has drawn desirable attention to the entire spectrum of disorders resulting in bladder pain. The wish to include all of them into one handy entity has unfortunately resulted in much scientific and clinical confusion, though. It is noted that originally interstitial cystitis represented the Hunner type of disease. Today, there is agreement that the classic type of interstitial cystitis with Hunner's lesions, bladder pain syndrome type 3C according to current terminology, stands out as a well-defined phenotype; it has to evaluated separately in clinical studies and practice, as treatment requirements differ importantly between this and other phenotypes., (© 2014 The Japanese Urological Association.)

Objective: Bladder pain syndrome/interstitial cystitis (BPS/IC) includes a heterogeneous collection of underlying pathological conditions. Compared to the classic IC with a Hunner lesion, now denominated ESSIC type 3C, the non-Hunner type of BPS/IC appears different in a number of respects. In a previous study, measuring luminal nitric oxide (NO) in the bladder of patients with BPS/IC, it was reported that all patients with ESSIC type 3C had high levels of NO. The aim of the present study was to investigate the source of inducible nitric oxide synthase (iNOS) and thereby the cellular origin of NO production via iNOS., Material and Methods: Immunohistochemistry, with two different anti-iNOS antibodies, was used to study 10 patients with BPS/IC ESSIC type 3C who expressed high levels of intraluminal NO. These results were compared with four patients with non-Hunner BPS/IC. To substantiate further the involvement of iNOS in this condition, the protein expression of nitrotyrosine, a marker for iNOS activation, was also assessed., Results: On routine histopathology, the tissues of type 3C patients exhibited inflammatory infiltrates of varying intensity. Strong immunoreactivity for both iNOS and nitrotyrosine was noted within the urothelium but also within the inflammatory infiltrates in the lamina propria of these subjects., Conclusions: The findings of a clearly detectable protein expression of iNOS in both the urothelium and the inflammatory infiltrates in bladder biopsies from patients with BPS/IC ESSIC type 3C suggest that the production of NO, in this entity, may occur in different tissue compartments.

Introduction: The concept of interstitial cystitis (IC) has changed dramatically during the last decades, eventually representing a symptom complex with varying contents. To include all patients with bladder pain, the umbrella term 'bladder pain syndrome' (BPS) has been suggested, incorporating the classic presentation of IC as a separate phenotype. This change of concepts has not been uncontroversial. Bladder pain syndrome often has a profound effect on the patients' quality of life. Generally, recognition of this problem complex is hampered by insufficient familiarity in the medical community. The correct diagnosis is often delayed by several years and may be preceded by multiple medical consultations and treatment attempts. There is no doubt that an early and correct diagnosis is of great significance for the patient., Areas Covered: In this article, a critical review of methods and means to approach the diagnosis is presented including some notes of current controversies., Expert Opinion: The key to an early diagnosis is symptom recognition. We are dealing with a heterogeneous concept including various phenotypes. The successful treatment requires understanding and expedient use of objective means, such as cystoscopy, biopsy and input from the multidisciplinary team. In the literature, limited evidence exists for the management of BPS/IC, due to heterogeneity in methodology and description of the syndrome(s). A more consequent use of available methods is desirable. For the immediate future, better understanding of the aetiology, pathogenesis and presentation of various BPS/IC phenotypes is indispensable.

Objective: This study aimed to assess mast cell density in the lamina propria for possible correlation with duration of symptom amelioration after transurethral resection of the bladder (TURB)., Material and Methods: Twelve patients (eight women and four men) referred to the tertiary referral facility, treated between June 2003 and June 2009, were included in the study. All had undergone three consecutive complete TURB procedures, where the first one was also diagnostic. All patients fulfilled the NIH-NIDDK criteria and the ESSIC bladder pain syndrome/interstitial cystitis type 3C criteria; they had Hunner's lesions and biopsy findings with inflammatory infiltrates, granulation tissue and mastocytosis. Bladder biopsies were evaluated for mast cell density by immunochemistry and symptom amelioration was recorded by self-report of symptom relapse., Results: Median mast cell density in the lamina propria at the first, second and third TURB was high. No statistically significant correlation between mast cell density in the urothelium, lamina propria or detrusor, and duration of symptom amelioration could be seen after the first, second or third TURB., Conclusion: Mast cell density does not appear to correlate with duration of symptom amelioration after complete transurethral resection of Hunner's lesions, either in the lamina propria or in the urothelium or detrusor.

Context: Opinions on how to best treat bladder pain/interstitial cystitis are ambiguous., Objective: To review previous and recent literature on this subject to assess the current state of evidence., Evidence Acquisition: With important previous papers reviewed for the 2003 European Association of Urology guidelines as background, the PubMed database was searched and articles published in 2003-2007 were reviewed and relevant ones were selected for detailed study., Evidence Synthesis: A large number of studies describing a variety of quite dissimilar therapeutic principles were retrieved. The various methods and level of evidence are summarised in tables. Only pentosan polysulfate sodium (oral and intravesical), amitriptyline, hydroxyzine, cyclosporin A, intravesical dimethyl sulfoxide, transurethral resection of visible Hunner lesions, and major reconstructive surgery reached a high degree of recommendation. However, a number of pitfalls hamper evaluation of the available information; a crucial one is that our understanding of basic mechanisms causing bladder pain is fragmentary. So far, we are faced with a large variety of hypotheses although it is difficult to identify the most relevant ones. In this respect, we are not much helped by the recent literature because many studies have poor descriptions of patients or are of a pilot character, with no follow-up by larger trials. Controlled studies are rather scarce. On the other hand, some good-quality studies following up positive pilot trials end up with negative results., Conclusion: Perhaps the most significant problem concerns inclusion and exclusion criteria in bladder pain syndrome/interstitial cystitis studies. At this stage, it is not too easy to communicate the wide available expert knowledge to the general audience. More sophisticated standards, capable of being generally used, have to come.

Purpose: Interstitial cystitis (IC) is one of the most bothersome conditions in urological practice. There are 2 subtypes, classic and nonulcer IC, with similar symptoms but different outcomes with respect to clinical course and response to treatment. Histologically there are fundamental differences between the 2 subtypes, classic IC presenting a severe abnormality of the urothelium and characteristic inflammatory cell infiltrates while inflammation is scant in nonulcer IC. Regulation of urinary nitric oxide synthase activity has been proposed to be of importance for immunological responses in IC. We present evidence of a profound difference between the 2 subtypes concerning nitric oxide production, mirroring the differences in inflammatory response in IC., Materials and Methods: A total of 17 patients with both subtypes and active disease as well as patients with disease in remission were included in the study, all diagnosed according to National Institute for Diabetes and Digestive and Kidney Diseases criteria. Luminal nitric oxide was measured in the bladder of patients using a chemiluminescence nitric oxide analyzer., Results: All patients with classic IC had high levels of NO. None of the other patients had any significant increase in NO levels in the bladder. The NO level in patients with classic IC was not related to symptoms but rather to the assignment to this specific subgroup of IC. The highest levels of NO were found in patients in the initial phase of classic IC., Conclusions: The difference in NO evaporation between classic and nonulcer IC allows for subtyping of cases meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria without performing cystoscopy. The findings in the present series together with previous findings clearly demonstrate that the 2 subtypes of IC represent separate entities. This separation further emphasizes the need to subtype all cases included in all scientific matters, ensuring that the 2 subtypes are evaluated separately in clinical studies.

Objectives: To evaluate the long-term continence rate, subjective satisfaction and treatment-associated morbidity in a carefully selected group of patients undergoing Stamey bladder neck suspension., Material and Methods: We studied 24 women with objectively validated genuine stress urinary incontinence (GSI) who were treated using the Stamey needle colposuspension method. Follow-up was performed by means of a questionnaire, a urodynamic assessment and a new standardized quantification test. Time to follow-up ranged from 28 to 100 months (mean 63 months)., Results: Of the 24 patients, 20 (83%) reported an improvement in clinical symptoms for a mean of 37 (range 12-84) months at the evaluation and 10 (42%) were completely continent after the Stamey procedure. Four patients (17%) reported a poor outcome of the operation, but in only one case could this be related to recurrent GSI. Treatment-associated morbidity was low but the frequency of postoperative urgency symptoms was higher than that reported in other studies (21%)., Conclusion: In a selected population of pure GSI patients with no demonstrable detrusor overactivity, the Stamey bladder neck suspension procedure appears a feasible therapeutic option with few complications.

Objective: When conservative treatment for bladder overactivity fails the "clam" ileocystoplasty has been proposed to restore continence and preserve urethral voiding. This study presents our experience with this technique., Materials and Methods: Thirty patients, 4 men and 26 women, with a mean age of 50.3 years (range 21-71 years) were operated upon. Five patients had an incomplete spinal lesion and detrusor hyperreflexia, 25 subjects had an idiopathic, unstable detrusor. The ileocystoplasty was combined with a colposuspension procedure in 8 patients. In one patient simultaneous repair of an urethro-vaginal fistula was performed using omentum flap interposition. The mean follow-up was 60 months (range 4-127)., Results: To the surgeon, 27 patients (90%) reported satisfaction with bladder control and relief of symptoms at follow-up. When asked by a nurse in a written questionnaire, 18 out of 23 patients (78%) were quite happy with their bladder function postoperatively. No serious complications to surgery were noted. Postoperatively, 11 patients used self-intermittent catheterization and one, by choice, preferred an indwelling catheter. Due to failure, two patients later underwent reoperation with urinary diversion and one further patient required an additional artificial sphincter. Metabolic consequences owing to enteric malabsorption were infrequent and of a mild nature. No malignant change was identified., Conclusion: In patients with refractory overactive bladder, we found the "clam" ileocystoplasty to be an effective technique for symptom reduction and increased quality of life.

Purpose: Interstitial cystitis is a chronic debilitating condition which mainly affects women. Accumulated evidence indicates that interstitial cystitis is a heterogeneous syndrome. The nonulcer subtype appears different than classic interstitial cystitis in regard to symptoms, and endoscopic and histological findings as well as response to various treatments. We further explore the neurogenic nature of this disease using indirect immunofluorescence to evaluate the presence and density of various autonomic and sensory nerve fibers., Materials and Methods: Specimens from the bladder wall of 6 patients with classic interstitial cystitis, 7 with nonulcer interstitial cystitis and 6 controls were evaluated to determine the presence and density of nerve fibers containing tyrosine hydroxylase, calcitonin gene-related peptide, neuropeptide Y and substance P using specific antibodies, and the general presence of nerve fibers using a mixture of antibodies against nerve filament, neuron specific enolase and S-100 protein., Results: Increased density and number of nerve fibers immunoreactive for tyrosine hydroxylase were noted in interstitial cystitis cases compared to controls. Furthermore, there was a difference between classic and nonulcer disease in the overall density of nerves using the antibody mixture., Conclusions: Our findings indicate an altered peripheral sympathetic innervation in interstitial cystitis cases, which may be an indication of primary neurogenic etiology. The difference in nerve density observed after incubation with the antibody mixture between classic and nonulcer interstitial cystitis supports the hypothesis that the 2 forms represent separate entities.

Interstitial cystitis (IC) is a chronic debilitating condition which mainly affects women. Accumulated evidence indicates that IC is a heterogeneous syndrome. As compared to classic IC, the non-ulcer type of IC appears to be different concerning symptomatic, endoscopical and histological findings, as well as in response to various forms of treatment. S-100 is a neural protein considered to be located primarily in the axons. To explore further the neurogenic nature of the disease, we compared bladder wall S-100 content in controls and in patients with classic and non-ulcer IC. We noticed a decrease in S-100 content in non-ulcer IC as compared to controls. This may be an expression of altered peripheral innervation in non-ulcer IC, which, in turn, may be an indication of primary neurogenic etiology. The difference in S-100 content between classic and non-ulcer IC supports the hypothesis that they represent separate entities, which may explain differences in response to various treatments.

Mucosal mast cells (MCs) are normally found in the connective tissue stroma but are redistributed into the epithelium in conditions associated with immunoglobulin E responses, such as allergic inflammation and nematode infections, as well as in interstitial cystitis, a condition of unknown etiology. The potential role of epithelium-derived factors in this response prompted this inquiry into growth and differentiation signaling in normal tissue as well as in tissues from five different metaplastic conditions of the urothelium (cystitic cystica, cystitis glandularis, colonic metaplasia, squamous cell metaplasia, and nephrogenic metaplasia). Expression of the two major human MC growth factors, stem cell factor (or kit ligand) and interleukin 6, was detected using immunohistochemistry. In the case of interleukin 6, its mRNA expression was also detected using in situ reverse transcription-polymerase chain reaction. Among the different metaplastic lesions, nephrogenic metaplasia was the only one associated with an abundance of MCs, which were distributed within or in close relationship to the epithelium. Unlike in the other types of metaplasia, the epithelium strongly co-expressed interleukin 6 and stem cell factor. The MCs expressed the stem cell factor receptor CD117 and exhibited a variable tryptase immunoreactivity, but lacked chymase. They also displayed a relative deficiency of granular glycosaminoglycan, as indicated by a lack of metachromasia, and were sensitive to strong aldehyde fixation. The findings suggest that the MC response in nephrogenic metaplasia may be the result of local epithelial stem cell factor/interleukin 6 expression.

Purpose: Interstitial cystitis is a chronic debilitating condition that mainly affects women. Accumulated evidence indicates that interstitial cystitis is a heterogeneous syndrome. The nonulcer type seems to respond less favorably to various conservative treatments than the classic type. Supratrigonal cystectomy with ileocystoplasty is established treatment for interstitial cystitis refractory to conservative treatment. We evaluate whether classic interstitial cystitis responds differently than nonulcer disease to subtotal bladder resection and ileocystoplasty., Materials and Methods: We evaluated 13 patients 27 to 79 years old with interstitial cystitis who underwent supratrigonal cystectomy and ileocystoplasty due to failure to respond to conservative treatment., Results: In all 10 patients with classic interstitial cystitis symptoms were relieved after ileocystoplasty. In the 3 patients with nonulcer interstitial cystitis pain remained, while the frequency of voiding somewhat decreased. In these patients trigonal resection and urinary diversion with a Kock pouch resolved the symptoms., Conclusions: Our study confirms that supratrigonal cystectomy with ileocystoplasty results in a good outcome in classic interstitial cystitis. However, this method seems to be unsuitable for nonulcer disease. Identification of the relevant subtype of interstitial cystitis is of crucial importance for selecting the appropriate method of lower urinary tract reconstruction.