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PURPOSE: In women symptoms of interstitial cystitis are difficult to distinguish from those of painful bladder syndrome and they appear to overlap with those of urinary tract infection, chronic urethral syndrome, overactive bladder, vulvodynia and endometriosis. This has led to difficulties in formulating a case definition for interstitial cystitis, and complications in the treatment and evaluation of its impact on the lives of women. We performed a systematic literature review to determine how best to distinguish interstitial cystitis from related conditions. MATERIALS AND METHODS: We performed comprehensive literature searches using the terms diagnosis, and each of interstitial cystitis, painful bladder syndrome, urinary tract infection, overactive bladder, chronic urethral syndrome, vulvodynia and endometriosis. RESULTS: Of 2,680 screened titles 604 articles were read in full. The most commonly reported interstitial cystitis symptoms were bladder/pelvic pain, urgency, frequency and nocturia. Interstitial cystitis and painful bladder syndrome share the same cluster of symptoms. Chronic urethral syndrome is an outdated term. Self-reports regarding symptoms and effective antibiotic use can distinguish recurrent urinary tract infections from interstitial cystitis in some but not all women. Urine cultures may also be necessary. Pain distinguishes interstitial cystitis from overactive bladder and vulvar pain may distinguish vulvodynia from interstitial cystitis. Dysmenorrhea distinguishes endometriosis from interstitial cystitis, although many women have endometriosis plus interstitial cystitis. CONCLUSIONS: In terms of symptoms interstitial cystitis and painful bladder syndrome may be the same entity. Recurrent urinary tract infections may be distinguished from interstitial cystitis and painful bladder syndrome via a combination of self-report and urine culture information. Interstitial cystitis and painful bladder syndrome may be distinguished from overactive bladder, vulvodynia and endometriosis, although identifying interstitial cystitis and painful bladder syndrome in women with more than 1 of these diseases may be difficult.
Chronic cystitis was diagnosed in 36% of children with neuromuscular ureteral dysplasia, in 69% of those with vesicoureteral reflux, in 42% of girls with urolithiasis. Recurrent inflammation was registered in 96, 11% of patients with fibrinous cystitis and catarrhal cystitis, respectively, and in 62% of girls with bullous cystitis. Histological examination of 130 biopsies of bladder mucosa from girls with frequent recurrences of chronic cystitis provided a clear morphological picture of each endoscopic cystitis form. In bullous cystitis there are 2 congenital variants of mucosal structure: overdevelopment of lymphoid tissue as massive lymphoid follicules and lymphangioectatic form. Catarrhal cystitis is characterized by vascular angiomatosis. All the patients with fibrinous cystitis had squamous cell epithelial metaplasia. Morphological findings evidence that fibrinous cystitis is the most severe and unfavorable form of cystitis, bullous cystitis is less severe while catarrhal cystitis is favorable.
OBJECTIVE: To evaluate the Interstitial Cystitis Symptom Index and Problem Index as a screening tool for interstitial cystitis, and to estimate the prevalence and risk factors for interstitial cystitis in women with chronic pelvic pain. METHODS: Forty-five women scheduled to undergo laparoscopy for chronic pelvic pain were recruited. Women were questioned about lower urinary tract symptoms, administered the Interstitial Cystitis Symptom Index and Problem Index, and rated pain symptoms on a 0-10 visual analogue scale. Cystoscopy with hydrodistension and bladder biopsy was performed at the time of laparoscopy. Interstitial cystitis was diagnosed if women had a combination of: 1) urgency, 2) frequency or nocturia, and 3) positive cystoscopic findings. RESULTS: Seventeen women (38%) were diagnosed with interstitial cystitis. A score of 5 or more on the Symptom Index had 94% sensitivity (95% confidence interval [CI] 71%, 99.8%) and 93% negative predictive value (95% CI 68%, 99.8%) in diagnosing interstitial cystitis. On multivariable analysis, an elevated Symptom Index score of 5 or more (odds ratio [OR] 9.4; 95% CI 1.01, 88.1) and an elevated dyspareunia score of 7 or more (OR 5.5; 95% CI 1.10, 27.1) were risk factors for interstitial cystitis. CONCLUSION: In our sample of women with chronic pelvic pain, the prevalence of interstitial cystitis was 38%. The Interstitial Cystitis Symptom Index was a useful screening tool. Independent risk factors for the diagnosis of interstitial cystitis were an elevated Symptom Index score and an elevated dyspareunia pain score. For women with chronic pelvic pain, screening for interstitial cystitis should be performed.
OBJECTIVES: To explore the antibiotic prescribing pattern for cystitis and the patient-related variables associated with prescription during a 4 year period among Italian general practitioners (GPs). METHODS: We obtained information from the 'Health Search Database' (HSD), an Italian general practice research database. From a total sample of 457 672 eligible patients aged >16 years registered up to December 2002, we included those whose diagnoses could be classified as acute (uncomplicated and complicated) and recurrent cystitis. Patients' features and prevalence of antibiotic users were assessed. RESULTS: Of 35 129 cases diagnosed during the period 1999-2002, 96.0% of them were acute cystitis (39.2% recorded as uncomplicated). The prevalence of cases with acute complicated and uncomplicated cystitis slightly increased during the 4 year period, whereas it remained stable for recurrent cystitis. Most of the cystitis cases reported no diagnostic tests. More than 70% of patients were prescribed with at least one antibiotic, with a 4-fold increased risk of antibiotic use for acute cystitis throughout the study period. The prevalence of antibiotic users reached 86.2% for both acute uncomplicated and complicated cystitis in 2002, and 81.5% for recurrent cystitis. Fluoroquinolones represented the most common antibiotics being prescribed although they markedly decreased during these years. Fosfomycin trometamol use increased dramatically, becoming the first choice for any type of cystitis. CONCLUSIONS: Data indicate an evident rise in antibiotic use mostly related to fosfomycin trometamol. They also indicate that such a prescriptive trend finds confirmation from the available evidence for acute uncomplicated cystitis, although the management of recurrent cystitis could be further improved.
PURPOSE: We examined neurotrophin and receptor tyrosine kinase (Trk) expression in the bladder and major pelvic ganglia (MPG) after cyclophosphamide induced cystitis in rats. MATERIALS AND METHODS: The bladder and MPG were used in immunohistochemical studies, enzyme-linked immunoassays and Western blots for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), TrkA and TrkB. Bladder postganglionic MPG cells were labeled by tracing techniques. RESULTS: NGF and BDNF expression was decreased in the bladder of all rats after cystitis (p < or =0.001). NGF and BDNF expression was increased in the MPG in male rats with cystitis (p < or =0.01). Cells expressing TrkA and TrkB immunoreactivity (IR) increased 78% to 81% in the MPG in male rats with cystitis. TrkA-IR or TrkB-IR bladder postganglionic cells increased 50% to 74% with cystitis. Cystitis increased TrkA-IR 5 to 10-fold and TrkB-IR 10 to 12-fold in detrusor muscle. TrkA-IR and TrkB-IR were prominent in control urothelium but decreased with cystitis. After cystitis TrkB-IR nerve fibers and TrkA-IR cellular infiltrates were more apparent compared to controls. CONCLUSIONS: Cystitis decreases bladder NGF and BDNF expression, whereas MPG expression is increased. This change may reflect neurotrophin release at the bladder and retrograde transport to the MPG. TrkA-IR and TrkB-IR are increased in bladder postganglionic cells and bladders with cystitis. This increase may reflect a shift in Trk staining from urothelium to detrusor muscle and nerve fibers with cystitis. Neurotrophin/Trk interactions in the bladder and MPG may contribute to bladder overactivity with cystitis.
This article is the fifth of a series aimed at mapping brain activities as they result from the development of cyclophosphamide (CP) cystitis in behaving rats using c-fos and Krox-24 expression. The inactive hepatic metabolites of CP are metabolized in the kidney to produce acrolein, which generates cystitis. Data come from animals which were injected once i.p. with either 1 ml saline (sham) or 100 mg/kg CP in 1 ml saline under transient volatile anesthesia and which behaved freely for 1-4 h postinjection, 4 h being the minimum time for cystitis to completely develop. Survival times longer than 4 h were not studied owing to ethical considerations. The first 2 h postinjection cover a period of time over which inputs of multifactorial origin (stress and pain due to the intraperitoneal injection process, possible effects due to the presence of hepatic CP metabolites in blood, cystitis onset) interact in an indistinguishable way; the last 2 h are more cystitis specific as the other effects have vanished. Complete screening of telencephalic levels has been performed. These data complete previously published data at both spinal and subtelencephalic levels. Of all the telencephalic structures, only the bed nucleus of the stria terminalis in the dorsal part of its lateral division (BSTLd) and, to a lesser degree, the nucleus centralis of the amygdala, mostly in its caudal portion (cCeA), appeared to be significantly driven over the most specific cystitis period. Both of these structures had related, but not identical patterns of expression. They both reacted shortly after CP injection, but, while cCeA maintained its activity throughout cystitis development, BSTLd showed a rebound, reaching a peak value when cystitis was fully developed. Both of these areas are the only telencephalic areas to contain high PACAP38 immunoreactivity. This is evidence that, (1) both the BSTLd and cCeA could be the most rostral areas that visceronociceptive inflow would reach when cystitis genesis is under way, and (2) PACAP38 could be one of the neurochemical agents involved in telencephalic visceronociceptive processing. From our complete mapping of brain activities under a fully developed cystitis situation (4 h postinjection), it appears that the activities in BSTLd and cCeA are concomitant with those of both the dorsal vagal complex (DVC), paratrigeminal nucleus (PaT), and the ventrocaudal bulbar reticular formation (vcBRF) at brainstem levels, suggesting they all form the main part of the neural network that subserves the central processing of cystitis-related inputs, comprising pain and associated pseudoaffective responses. Both the DVC and BSTLd, which are the most powerfully driven areas, would be particularly important in such a way. The origin of these activities should be found in both vagal (as sensed through PaT activity) and spinal (pelvic) influences. This network profoundly differs from those reported for painful situations, either somatic or visceral, which controversally accompany positive cardiac inotropism.
PURPOSE: Questionnaires for the evaluation of interstitial cystitis are widely used, but their value in discriminating interstitial cystitis from other diagnoses among patients with urological symptoms has not been determined. We assessed the validity of 2 frequently used interstitial cystitis questionnaires-the O'Leary-Sant Symptom Index and Problem Index and the Pain, Urgency, Frequency Symptom Scale-for screening for interstitial cystitis. MATERIALS AND METHODS: The Pain, Urgency, Frequency Symptom Scale and the O'Leary-Sant Symptom Index and Problem Index were administered to the same 220 patients at a urology clinic before diagnosis. Questionnaire scores between patients with and without interstitial cystitis, as well as among diagnostic groups, were compared by parametric and nonparametric analyses. Receiver operating characteristic curves were constructed to determine the efficiency of each questionnaire in discriminating between patients with and without interstitial cystitis. RESULTS: Interstitial cystitis was distinguishable from the other diagnoses using both questionnaires (p <0.001). Separate analyses of bother and symptom scores yielded similar results. Receiver operating characteristic curves demonstrated the Pain, Urgency, Frequency Symptom Scale to be more efficient than the O'Leary-Sant Symptom Index and Problem Index in detecting interstitial cystitis in this population with an optimal cutoff value of 13 or greater. CONCLUSIONS: While the Pain, Urgency, Frequency Symptom Scale and the O'Leary-Sant Symptom Index and Problem Index questionnaires distinguish interstitial cystitis from other urinary tract pathologies, neither questionnaire demonstrates sufficient specificity to serve as the sole diagnostic indicator. These questionnaires should not be used to define interstitial cystitis, but can be used to screen patients with urinary tract symptoms to identify those who should be further examined for interstitial cystitis or to follow those who have already been diagnosed.
PURPOSE: We systematically identified and evaluated various animal models that have been studied to help identify the underlying mechanisms of and possible treatment options for interstitial cystitis. MATERIALS AND METHODS: Models of interstitial cystitis published between 1983 and 2001 were obtained by searching MEDLINE and other Internet databases using cystitis and model as the primary key words. Models with characteristics of interstitial cystitis similar to those defined by National Institutes of Arthritis, Diabetes, Digestive and Kidney Diseases criteria were reviewed. Some articles describing animal models with similar pathological conditions in other organs were also included to enlarge the base of potentially relevant material. RESULTS: We identified and evaluated some 16 animal models of interstitial cystitis, which we categorized as bladder inflammation induced by intravesical administration of an irritant or immune stimulant, systemic and environmentally induced inflammation, and a naturally occurring model of interstitial cystitis that occurs in cats. Some abnormalities identified in humans and cats with interstitial cystitis can be reproduced in healthy animals using luminal, systemic or environmental stimuli. At the level of the bladder the source of stimulation cannot be discriminated. Variability in the extent of bladder distention complicated the interpretation of some studies. In addition, the noxious stimuli used can affect many epithelial surfaces as well as the urothelium, suggesting they are nonspecific responses to injury rather than specific to interstitial cystitis. CONCLUSIONS: No model in bladder injury in healthy animals currently reproduces as many features of interstitial cystitis as the naturally occurring disease in cats. While induced models of relative injury may help to provide insight into the bladder response to injury, feline interstitial cystitis follows a similar chronic waxing and waning time course as does interstitial cystitis in humans, which may be more suitable for studying the effects of stressors on the severity of clinical signs as well as newly proposed therapies.
PURPOSE: GP51 is a urinary glycoprotein with a molecular weight of 51 kDa. This glycoprotein is produced and secreted by the transitional epithelium of the genitourinary tract, and has been isolated from human urine. Studies have demonstrated that GP51 levels are decreased in bladder biopsies of patients with interstitial cystitis. We evaluated urinary GP51 in a noninvasive manner as a clinical marker of interstitial cystitis. MATERIALS AND METHODS: Urinary GP51 levels were measured using antigen inhibition enzyme-linked immunosorbent assay. In blinded fashion we analyzed for quantitative differences 24-hour urine samples of 36 patients with interstitial cystitis and 23 normal controls who were age matched within 5 years (mean age 47.3). We also evaluated GP51 in random urine specimens of 17 normal controls, 14 patients with interstitial cystitis and 11 subjects who had undergone cystectomy to determine whether urinary GP51 is mainly produced by the bladder, which is the site of interstitial cystitis. To ascertain the specificity of urinary GP51 to interstitial cystitis urine samples of 34 patients with other urological diseases were measured and compared with findings in the samples of 15 with interstitial cystitis. RESULTS: Low GP51 levels appeared to be unique to the interstitial cystitis state compared to normal (p = 0.008). GP51 in patients with interstitial cystitis and in those who underwent cystectomy was lower (p < 0.001) than in normal controls. These findings suggest that the major source of urinary GP51 is the bladder. Also, we observed lower GP51 levels in interstitial cystitis than in other urinary tract diseases (p < 0.0001). CONCLUSIONS: Our study substantiates the possibility of using GP51 as a clinical marker for diagnosing interstitial cystitis by a noninvasive urinary assay.
Interstitial cystitis is a chronic inflammatory disorder of the urinary bladder that predominantly afflicts middle-age women. The end stage of the disease is ulceration of the urothelium, the so-called Hunner's ulcer. The aetiology of interstitial cystitis remains obscure. We have studied bladder biopsies from 22 cases of interstitial cystitis and control groups consisting of six cases of bacterial cystitis and eight healthy women. Indirect immunofluorescence was performed on the biopsies using murine MoAbs to human HLA class I molecules, and class II molecules, HLA-DP, HLA-DQ and HLA-DR. In interstitial cystitis, bacterial cystitis and normal controls most cells expressed HLA class I products. In six cases of interstitial cystitis and one case of bacterial cystitis there was evidence of HLA class I hyperexpression. In normal bladder and bacterial cystitis HLA class II expression was restricted to submucosal dendritic cells, Langerhans cells macrophages, vascular endothelial cells and activated lymphocytes. All but two cases of interstitial cystitis showed surface expression of HLA-DR (but not HLA-DP or DQ). In all cases of interstitial cystitis there was an increase in the numbers of macrophages, activated lymphocytes and vascular endothelial cells expressing HLA class II molecules within the submucosa. These findings provide further evidence for the importance of inappropriate HLA molecule expression in a disease suspected of having an autoimmune pathogenesis and where cellular autoimmune mechanisms play a decisive role in the destruction of the target cells--the bladder urothelium.
PURPOSE: The etiology of interstitial cystitis is unknown. We previously identified an interstitial cystitis urine factor, antiproliferative factor, that inhibits proliferation of bladder epithelial cells in vitro and complex changes in epithelial growth factor levels, including profound decreases in heparin-binding epidermal growth factor-like growth factor (HB-EGF). Bladder and renal pelvic catheterization of patients with interstitial cystitis indicated that the antiproliferative factor is made and/or activated in the distal ureter or bladder. Therefore, we determined whether bladder epithelial cells from interstitial cystitis cases produced the antiproliferative factor and whether purified antiproliferative factor could alter production of growth factors known to be abnormal in interstitial cystitis. MATERIALS AND METHODS: Antiproliferative factor activity was determined by 3H-thymidine incorporation into primary bladder epithelial cells. The antiproliferative factor was purified by size fractionation followed by sequential chromatography involving ion exchange, hydrophobic interaction and high performance liquid chromatography. HB-EGF, epidermal growth factor, insulin-like growth factor and insulin-like growth factor binding protein 3 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Bladder epithelial cells from patients with interstitial cystitis produced a single antiproliferative factor with the same purification profile as that purified from interstitial cystitis urine. Purified antiproliferative factor specifically inhibited HB-EGF production by bladder epithelial cells in vitro, and the effect of interstitial cystitis urine or purified antiproliferative factor on bladder cell proliferation was inhibited by recombinant human HB-EGF in a dose dependent manner. Similar to urine HB-EGF, serum HB-EGF was also significantly lower in interstitial cystitis cases than in controls. CONCLUSIONS: Bladder epithelial abnormalities in interstitial cystitis may be caused by a negative autocrine growth factor that inhibits cell proliferation by down-regulating HB-EGF production. Furthermore, decreased levels of urine and serum HB-EGF indicate that interstitial cystitis may be a urinary tract manifestation of a systemic disorder.
The bladder mast cell contains many granules, each of which can secrete many vasoactive and nociceptive molecules. A number of conditions, such as extreme cold, drugs, neuropeptides, stress, trauma, and toxins, can trigger the mast cell to secrete some of its contents; they, in turn, can sensitize sensory neurons, which can further activate mast cells by releasing neurotransmitters or neuropeptides. Additionally, the mast cell can directly cause vasodilation and bladder mucosa damage while also attracting inflammatory cells, thus causing many of the problems seen in interstitial cystitis. The mast cell appears to be involved in the pathogenesis of interstitial cystitis. Although it is not pathognomonic of the disease, mastocytosis does occur in a significant subset of interstitial cystitis patients. Because interstitial cystitis is now regarded as a syndrome caused by multiple factors, it is conceivable that one cause of interstitial cystitis is associated with bladder mastocytosis and mast cell activation. The fact that mast cells are also increased in patients with transitional cell carcinoma of the bladder does not diminish the importance of mastocytosis in interstitial cystitis, because the mast cells are not activated in carcinoma but are activated in interstitial cystitis. Perhaps the common strand between these two bladder diseases is the putative allergens/carcinogens in bladder urine that breach the protective lining of the bladder and then elicit an immune response in the bladder wall. Furthermore, the majority of patients with a history of bladder tumors receive multiple courses of intravesical chemotherapy (such as thiotepa) or immunotherapy (bacille Calmette-Guerin), and it is possible that these agents damage the bladder lining or provoke an inflammation in the bladder wall. The theory of a defective/deficient bladder glycosaminoglycan layer in interstitial cystitis is also consonant with this putative chain of events in the pathogenesis of interstitial cystitis. Thus these two theories interstitial cystitis causation--a glycosaminoglycan deficiency and bladder mastocytosis--may well operate in concert to cause bladder inflammation and the symptoms of interstitial cystitis. Clinicians may be at a distinct disadvantage because they are faced with a multitude of potential mast cell triggers and numerous mediators secreted. It may, therefore, be advisable to block or inhibit the mast cell from responding to many of these various stimuli. Specific mast cell mediators should be assayed as possible diagnostic tools, and potential mast cell inhibitors should be tried under controlled conditions to determine the extent of therapeutic benefit.
PURPOSE: Levels of uronate, a basic component of urothelial glycosaminoglycans, are increased in urine specimens of patients with interstitial cystitis with severe symptoms. In this study we examined the urinary glycosaminoglycan profile and correlated the profile and urinary hyaluronic acid (a glycosaminoglycan) levels with symptom severity. MATERIALS AND METHODS: Urine specimens and completed O'Leary-Sant interstitial cystitis symptom and problem indexes questionnaires were obtained from 29 patients with interstitial cystitis, 14 normal individuals, and 14 patients with other benign pelvic and bladder conditions. Patients with interstitial cystitis were divided into group 1-1 or both indexes less than 50% maximum score, and group 2-both indexes 50% of maximum score or greater. All patients met the National Institutes of Diabetes and Digestive and Kidney Diseases criteria except regarding glomerulation. In a followup study 30 urine specimens were collected from 8 patients with interstitial cystitis and from 4 normal individuals during 12 months. The urinary glycosaminoglycan profile was determined by gel filtration chromatography. Glycosaminoglycan peaks were analyzed by polyacrylamide gel electrophoresis. Urinary hyaluronic acid levels were determined by the hyaluronic acid test. RESULTS: Group 2 urine specimens contained 3 uronate peaks, whereas urine specimens from normal individuals and patients in group 1 contained 1 or 2 peaks. Peak 1 consisted of macromolecular glycosaminoglycans whereas peaks 2 and 3 contained oligosaccharides. Urinary hyaluronic acid levels were 3 to 4-fold increased in group 2. Glycosaminoglycan profile and hyaluronic acid levels detected interstitial cystitis severity with 83% sensitivity, and 89.7% and 74.4% specificity, respectively. Interstitial cystitis urothelial cells/tissues also over expressed hyaluronic acid synthase 1 (which synthesizes hyaluronic acid) compared to normal urothelial cells/tissues. In the followup study urinary uronate levels, glycosaminoglycan profile and hyaluronic acid levels detected patients with severe symptoms with 73% sensitivity and 87% to 94% specificity. In both studies uronate, glycosaminoglycan profile and hyaluronic acid levels significantly correlated with interstitial cystitis severity (p <0.001). CONCLUSIONS: Urinary glycosaminoglycan profile, uronate content and hyaluronic acid levels are potentially useful markers for monitoring interstitial cystitis severity, and are likely to be involved in interstitial cystitis pathophysiology.
The diagnosis of interstitial cystitis is primarily made based on clinical and cystoscopic findings with exclusion of other bladder diseases. Despite all of the efforts at definitive identification, interstitial cystitis lacks universal objective findings. Mast cell activation with associated histamine release has been postulated as an etiological factor leading to the symptom complex associated with interstitial cystitis. To investigate this hypothesis, a 3-step controlled prospective study was conducted. In step 1 reliability of urine histamine assay was critically examined, and the assay was established to be simple, reliable and valid. In step 2 random spot urine histamine levels (basal state) were measured in 25 noninterstitial cystitis and 15 interstitial cystitis patients (22.1 +/- 0.95 ng./ml. versus 19.2 +/- 1.19 ng./ml.). There was no significant difference in the random urine histamine levels between the 2 groups (p greater than 0.05). In step 3 urine histamine levels were measured before and after hydrodistention (acute stimulation) in 7 noninterstitial cystitis controls and 6 newly diagnosed interstitial cystitis patients under general anesthesia. The urine histamine-to-creatinine ratio was used to correct for the dilutional effect of normal saline used during hydrodistention. The urine histamine-to-creatinine ratios of the control group showed no significant difference before and after hydrodistention. However, the difference in the urine histamine-to-creatinine ratios of the interstitial cystitis group compared to the controls before and after hydrodistention was highly significant (p less than 0.001). Although measurement of random spot urine histamine alone (basal state) was not found useful to make the diagnosis of interstitial cystitis, measurement of urine histamine before and immediately after hydrodistention (acute stimulation) may become an important objective parameter to assist in the diagnosis of interstitial cystitis.
PURPOSE: The etiology of interstitial cystitis is unknown. Urine from patients with interstitial cystitis has been shown to inhibit urothelial proliferation through a putative antiproliferative factor and to contain decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared to controls. Stretch of detrusor smooth muscle cells is known to stimulate HB-EGF production. Because bladder hydrodistention sometimes alleviates the symptoms of interstitial cystitis, we determined whether the stretch stimulus of hydrodistention alters antiproliferative factor activity and/or HB-EGF in interstitial cystitis urine specimens. MATERIALS AND METHODS: Urine was collected immediately before, and 2 to 4 hours and 2 weeks after hydrodistention from 15 patients with symptoms and cystoscopic findings compatible with interstitial cystitis and 13 controls. Hydrodistention was performed with the subject under general or regional anesthesia and bladders were distended to 80 cm. water 3 times. Urinary HB-EGF was measured by enzyme-linked immunosorbent assay and urinary antiproliferative factor activity was determined by measuring 3H-thymidine uptake by normal human bladder urothelial cells. RESULTS: Hydrodistention significantly increased urinary HB-EGF in patients with interstitial cystitis toward normal control values (before distention p = 0.003, 2 weeks after distention p = 0.67). Urine antiproliferative factor activity decreased significantly after hydrodistention in patients with interstitial cystitis. However, antiproliferative factor activity in interstitial cystitis and control specimens was still statistically different 2 weeks after distention (before distention p = 0.0000004, 2 weeks after distention p = 0.04). CONCLUSIONS: Bladder stretch increased HB-EGF and conversely reduced antiproliferative factor activity in urine from patients with interstitial cystitis but not controls up to 2 weeks after distention. These results provide additional evidence for the possible role of antiproliferative factor and decreased HB-EGF in the pathophysiology of interstitial cystitis. To our knowledge this is also the first human study to show that in vivo bladder stretch can alter urinary factors that regulate cell growth.
Hematopoietic stem cell transplant recipients frequently develop BK virus (BKV)-associated hemorrhagic cystitis, which coincides with BK viruria. However, the precise role of BKV in the etiology of hemorrhagic cystitis in hematopoietic stem cell transplant recipients remains unclear, since approximately 50% of all such adult transplant recipients excrete BKV, yet do not develop this clinical condition. In the present study, BKV were analyzed to determine if mutations in the non-coding control region (NCCR), and specific BKV sub-types defined by sequence analysis of major capsid protein VP1, were associated with development of hemorrhagic cystitis in hematopoietic stem cell transplant recipients. The regions encoding VP1 and NCCRs of BKV in urine samples collected from 15 hematopoietic stem cell transplant recipients with hemorrhagic cystitis and 20 without this illness were amplified and sequenced. Sequence variations in the NCCRs of BKV were identified in urine samples from those with and without hemorrhagic cystitis. Furthermore, five unique sequence variations within transcription factor binding sites in the canonical NCCR, O-P-Q-R-S, were identified, representing new BKV variants from a population of cloned quasi-species obtained from patients with and without hemorrhagic cystitis. Thirty-five BKV VP1 sequences were analyzed by phylogenetic analysis but no specific BKV sub-type was associated with hemorrhagic cystitis. Five previously unrecognized naturally occurring variants of the BKV are described which involve amplifications, deletions, and rearrangements of the archetypal BKV NCCRs in individuals with and without hemorrhagic cystitis. Architectural rearrangements in the NCCRs of BKV did not appear to be a prerequisite for development of hemorrhagic cystitis in hematopoietic stem cell transplant recipients.
Although cystitis glandularis has been considered a premalignant lesion, the instance of cystitis glandularis progression to adenocarcinoma or cystitis glandularis associated with adenocarcinomatous change is rare. This article includes 4 cases of neurogenic bladder with urinary diversion for different periods of time. In the first case with ureterocutaneostomy for twenty-five years diffuse cystitis glandularis with multifocal adneocarcinomatous change developed. The second case with suprapubic cystostomy for twenty-two years had diffuse cystitis glandularis of gastrointestinal type without evidence of malignancy. The other 2 cases with suprapubic cystostomy for merely ten years showed only mild to moderate cystitis glandularis and chronic cystitis with squamous metaplasia, respectively. The extent of cystitis glandularis appeared to correlate with the duration of urinary stasis. Ureterocutaneostomy rendered constant infection of the urinary bladder of the first case because of inadequate drainage. Thus, we assume that the intensity of the infection with a toxic product and virulence of organism may be responsible for the development of adenocarcinoma in this patient. Cystitis glandularis, especially diffuse type, can undergo malignant degeneration under constant irritation, but it is a long-term process.