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Once believed to be rare, interstitial cystitis is actually a common disorder in women and men. Using newly defined criteria, new tools for diagnosis, and a 3-part program to restore epithelial function, inhibit neural activation, and control allergies, urologists can successfully identify and treat most patients with this chronic progressive condition. [ABSTRACT FROM AUTHOR]

Objective: To determine whether patients with interstitial cystitis have elevated levels of toxic urinary cations, to identify and quantify these cationic metabolites, and to assess their cytotoxicity., Methods: Isolation of cationic fraction was achieved by solid phase extraction using an Oasis MCX cartridge on urine specimens from interstitial cystitis patients and controls. C 18 reverse phase high-performance liquid chromatography was used to profile cationic metabolites, and they were quantified by the area under the peaks and normalized to creatinine. Major cationic fraction peaks were identified by reverse phase high-performance liquid chromatography and liquid chromatography-mass spectrometry. HTB-4 urothelial cells were used to determine the cytotoxicity of cationic fraction and of individual metabolites., Results: The reverse phase high-performance liquid chromatography analysis was carried out on cationic fraction metabolites isolated from urine samples of 70 interstitial cystitis patients and 34 controls. The mean for controls versus patients was 3.84 (standard error of the mean 0.20) versus 6.71 (0.37) mAU*min/µg creatinine, respectively (P = 0.0001). The cationic fraction cytotoxicity normalized to creatinine for controls versus patients in mean percentage was -7.79% (standard error of the mean 3.32%) versus 20.03% (standard error of the mean 2.75%; P < 0.0005). The major toxic cations were 1-methyladenosine, 1-methylguanine, N 2 ,N 2 -dimethylguanosine and L-tryptophan., Conclusions: These data confirm significant elevation of toxic cations in the urine of interstitial cystitis patients. These toxic cations likely represent a primary cause of interstitial cystitis, as they can injure the bladder mucus and initiate an epithelial leak., (© 2020 The Japanese Urological Association.)

Objective: Treatment of chronic idiopathic scrotal pain is a dilemma and challenge. Many men with this condition undergo multiple therapies and surgeries with no improvement in their symptoms. Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) have a variable clinical presentation and initially complain of only one symptom of urinary urgency, frequency, or pain. We report on patients with chronic idiopathic scrotal pain treated with standard therapy for IC/BPS., Patients and Methods: Patients with chronic idiopathic scrotal content pain were evaluated, determined to have chronic idiopathic scrotal content pain, and were treated with either pentosan polysulfate sodium (PPS) or bladder instillations of alkalinized lidocaine and heparin., Results: Sixteen males were determined to have chronic idiopathic scrotal pain. Eight males received PPS and eight males received a bladder instillation of alkalinized lidocaine and heparin. All patients had improvement of their scrotal pain to a self-reported acceptable level., Conclusions: Chronic idiopathic scrotal pain may be one of the variable presenting symptoms of IC/BPS. This scrotal pain may actually be referred pain from the bladder. Standard therapies for IC/BPS may be a treatment option for chronic idiopathic scrotal pain., Competing Interests: There are no conflicts of interest.

Purpose: To identify and quantify toxic urinary cations in male patients with bladder pain syndrome/interstitial cystitis versus male controls, to compare them in symptomatic patients to those significantly improved, and to evaluate cytotoxicity of these cations to cultured urothelial cells to determine whether Tamm-Horsfall protein (THP) can neutralize the cations., Methods: Isolation of cationic fraction (CFs) was achieved by solid phase extraction on urine specimens of 51 male patients with IC and 33 male controls. C 18 reverse-phase high-performance liquid chromatography was used to profile and quantify cationic metabolites. Major CF peaks were identified by liquid chromatography-tandem mass spectrometry. HTB-4 urothelial cells were used to determine the cytotoxicity of CFs, individual metabolites, and of metabolite mixture with THP of patient versus THP of control subject., Results: CF content was significantly higher in patients compared to controls (p < 0.001). Patients had higher levels of modified nucleosides, amino acids, and their derivatives compared to controls. Cytotoxicity for control versus patient mean (SEM) percent was 1.7 (2.9) % versus 63.0 (3.7) %, respectively, (p < 0.001). Cytotoxicity of metabolites was reduced in the presence of THP of control compared to THP of patient (p < 0.001)., Conclusions: Patients with IC had significantly higher levels of cationic metabolites with higher cytotoxicity compared to controls. THP of these patients had reduced ability to sequester cytotoxicity of cationic metabolites. Patients who significantly improved on therapy had the same levels and toxicity of cationic metabolites as symptomatic males, suggesting that these cations may be the cause of epithelial dysfunction in IC.

Prepubertal mammary development involves elongation and branching of ducts and stromal tissue remodeling. This process is highly regulated and in mice is known to be affected by the presence of innate immune cells. Whether or not such immune cells are present or involved in bovine mammary development is unknown. For the first time, we determined the presence, location (relative to mammary ductal structures), and changes in numbers of eosinophils, mast cells, and macrophages in prepubertal bovine mammary tissue, and evaluated the effects of age, ovariectomy, and exogenous estrogen on numbers of each cell type. Chemical stains and immunofluorescence were used to identify the 3 cell types in formalin-fixed, paraffin-embedded mammary tissue from prepubertal female calves from 3 archived tissue sets. The ontogeny tissue set included samples of mammary tissue from female calves (n=4/wk) from birth to 6 wk of age. The ovary tissue set contained samples from ovary intact and ovariectomized heifers allowing us to investigate the influence of the ovaries on immune cells in the developing mammary gland in prepubertal heifers. Nineteen animals were intact or ovariectomized 30 d before sampling; they were 90, 120, or 150 d old at the time of sampling. A third tissue set, the estrogen set, allowed us to determine the effect of exogenous estrogen on innate immune cells in the gland. Eosinophils were identified via Luna staining, mast cells by May-Grunwald Giemsa staining, and macrophages with immunofluorescence. Key findings were that more eosinophils and mast cells were observed in near versus far stroma in the ontogeny and ovary tissue sets but not estrogen. More macrophages were observed in near versus far stroma in ontogeny animals. Eosinophils were more abundant in the younger animals, and fewer macrophages tended to be observed in ovariectomized heifers as compared with intact heifers and estrogen treatment resulted in a reduction in cell numbers. In summary, we show for the first time that innate immune cells are present in prepubertal bovine mammary tissue, localization varies by immune cell type, and abundance is related to proximity of epithelial structures and physiological state. We suggest a likely role for these cells in control of bovine mammary growth and ductal development., (Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Research has shown that prepubertal heifers experience allometric mammary growth that is influenced by the ovaries. Our purpose was to determine the role of estrogen in prepubertal mammary gland development. Sixteen Holstein calves were randomly assigned to 1 of 2 treatment groups: tamoxifen-injected (TAM) or control (CON). Calves were administered the antiestrogen tamoxifen (0.3 mg kg(1) d(1)) or placebo from 28 to 120 d of age. At 120 d, calves were euthanized and udders removed. Weight and DNA content of trimmed parenchymal tissue were halved (P ≤ 0.0001) in TAM compared with CON calves. Parenchymal samples from 3 zones of the left rear mammary gland (lower, middle, and outer regions) were processed for immunohistochemical staining for estrogen receptor α (ESR1) and progesterone receptor (PGR), Ki67-positive cells, and 5-bromo-2'-deoxyuridine label retaining cells (LRCs). Overall, neither the percentage nor location within the epithelial tissue layer of either ESR1- or PGR-positive cells was impacted by TAM treatment. However, image analysis indicated a 6.2-fold lower (P = 0.0001) level of ESR1 protein expression in TAM calves. Similarly, messenger RNA expression of ESR1 was also reduced (P = 0.0001) in TAM heifers. In contrast, expression of PGR protein was greater by 43% (P = 0.03) in TAM calves, but messenger RNA expression did not differ between treatments. Overall, TAM calves had a higher (P ≤ 0.03) percentage and density (cells per tissue area) of Ki67-positive cells. Irrespective of treatment, there were also more Ki67-labeled cells in the outer zones of the mammary gland (P ≤ 0.001). We were able to effectively use multispectral imaging to identify positive cells and quantify the expression of ESR1 and PGR protein. We also identified and counted the proportion of label retaining cells (LCR) (putative epithelial stem cells). We noted an overall 2.9-fold greater number of LRCs in TAM heifers and more LRCs in the outer sampling zones. This suggests that a cohort of LCR cells in TAM remained inactivated in comparison with CON heifers, which exhibited markedly increased growth of the mammary parenchymal tissue over the treatment period. These results suggest that the impacts of ovariectomy are partially explained by loss of ESR1 expression and/or estrogen receptor signaling in the prepubertal bovine mammary gland. The significance of mammary expression of PGR in control of prepubertal bovine mammary development remains unresolved., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Interstitial cystitis (IC) does not start as an endstage disease, it has a beginning when symptoms are milder, intermittent and the disease is misdiagnosed. To determine how IC develops patients were interviewed on when their symptoms began, what they were and are now as well as the various diagnoses that they received before they were determined to have IC., Methods: One hundred female IC patients were screened. They filled out a questionnaire asking about the age their disease presented, their initial and current symptoms, what their original diagnoses were, effect of the menstrual cycle and sexual activity on their symptoms and about any relatives with bladder symptoms or a current diagnosis of IC., Results: By age 30, 81% of patients had bladder symptoms, 21% before age 10. The first symptom was frequency in 81%, pain present in 59% and the symptoms were intermittent in 64%. Most common early misdiagnosis was UTI in 74% with 93% reporting negative urine cultures. Sex was painful and causes symptom flares in 82%, symptoms flared the week before the menses in 75%. Most common gynecologic diagnosis was yeast vaginitis, 42%. Urge incontinence was present in 33%. There were 51% that reported bladder symptoms in a first degree female relative., Conclusions: IC begins primarily with frequency and is intermittent in most patients with symptom flares associated with sexual activity. Pain and urgency incontinence tend to be a later symptoms. When IC flares the most common misdiagnosis is UTI. Symptoms begin before age 30 in most but an IC diagnosis is often not made until age 40. Genetics appear to play a significant role. It is important to consider these facts when evaluating women with "early IC" because correct diagnosis will result in proper therapy and reduced health care costs.

Tamm-Horsfall protein (THP) is theorized to play a critical role in preventing kidney stone formation. There is conflicting literature on THP analysis in kidney stone patients; therefore, this study was conducted using sensitive and specific bio-analytical techniques to better understand differences in THP, which play a potential role in nephrolithiasis pathogenesis. THP was isolated from urine samples of 34 male and 19 female kidney stone patients and 30 male and 24 female control subjects using diatomaceous earth. Protein was quantified by Superdex-200 size-exclusion chromatography. Sialic acid was determined by 1,2-diamino-4,5-methylenedioxybenzene high-performance liquid chromatography. Neutral and amino sugars were determined by high pH anion-exchange chromatography (HPAEC) with pulsed amperometric detection. THP N-glycans were derivatized with 2-aminobenzamide (2-AB) and profiled by HPAEC with fluorescence detection. N-glycan structures were confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results indicate that kidney stone patients had 32% lower protein content compared to controls, while sialic acid content was lower by 29 and 24% in male and female kidney stone patients, respectively, compared to controls. The neutral and amino sugars were also lower by 18 and 20% for male and female kidney stone patients, respectively, compared to controls. All results were statistically significant (p<0.001). These results are supported by 2-AB profiling of THP N-glycans and by MALDI-TOF MS of highly sialylated N-glycans in the range of m/z 3000-6000. This study demonstrates quantitative and qualitative differences in THP, which can be crucial contributing factors for nephrolithiasis.

Introduction: Interstitial cystitis (IC), sometimes referred to as IC/bladder pain syndrome, is a substantial health care problem. Once considered a rare, orphan disease, it is now believed to be relatively common. This pilot study was undertaken to determine if the combination of heparin and alkalinized lidocaine (heparin-lidocaine) was more efficacious than alkalinized lidocaine at relieving pain and urgency symptoms associated with IC and also capable of yielding higher lidocaine absorption., Materials and Methods: A single blind study was conducted on 14 IC patients with a heparin-lidocaine combination versus alkalinized lidocaine instilled intravesically. In a separate study serum lidocaine levels for heparin-alkalinized lidocaine combination versus USP lidocaine only were determined by high performance liquid chromatography., Results: Alkalinized lidocaine and heparin have been reported to provide relief from pain and urgency symptoms associated with IC. The heparin-lidocaine combination significantly reduced the % of bladder pain (38% versus 13%, p = 0.029) and urgency (42% versus 8% p = 0.003) compared to lidocaine. In addition the GAR was significantly better for the heparin-lidocaine combination at both 1 hr % improved (77% versus 50%, p = 0.04) and 24 hrs (57% versus 23%, p = 0.002) after study drug treatment. Serum lidocaine levels for the heparin-lidocaine combination were significantly higher compared to USP lidocaine (unalkalinized). The mean +/- SEM was 0.45 +/- 0.09 µg/mL and 0.20 +/- 0.05 µg/mL, respectively (p = 0.019)., Conclusions: In this pilot study the heparin-lidocaine combination results in significantly better relief of IC symptoms compared to alkalinized lidocaine and the combination yields higher lidocaine absorption than USP lidocaine.

Mammary growth and development depends on ovarian steroids and particularly interaction of estrogen and progesterone with their intracellular receptors. The objectives of this study were to determine the effect of ovariectomy on the expression of protein and messenger RNA for estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) and their relation to mammary ductal development and cell proliferation. Prepubertal Holstein heifers 2, 3, or 4 mo of age were randomly assigned to one of 2 treatments, ovariectomized (OVX; n = 8) or sham operated (INT; n = 12). Mammary parenchymal (PAR) tissue samples were harvested 30 d after surgery. Localization and quantitation of ESR1 and PGR in PAR were determined by immunohistochemistry and quantitative multispectral imaging. Relative messenger RNA expression of ESR1 and PGR in PAR was measured by quantitative real time polymerase chain reaction. We observed the complete absence of PGR-positive epithelial cell nuclei and reduced PGR transcript abundance in mammary parenchyma of OVX heifers. The percent of epithelial cells expressing ESR1 did not differ by treatment but was decreased with age. However, average intensity of ESR1 expression per cell was reduced in OVX heifers. The abundance of Ki67 labeled epithelial cells and stromal cells was reduced after ovariectomy. These data suggest that reduced mammary development after ovariectomy may be mediated by loss of PGR expression and reduced ESR1 expression in positive cells. A presumptive relationship with ovarian-derived circulating estradiol remains unresolved, but data suggest other ovarian-derived agents may play a role. Use of specific antagonists to manipulate expression or action of PGR and ESR1 receptors should provide direct evidence for roles of these receptors in prepubertal bovine mammary development., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To identify and characterise urinary cationic metabolites, defined as toxic factors, in patients with interstitial cystitis (IC) and in control subjects. To evaluate the cytotoxicity of the urinary cationic metabolite fraction of patients with IC vs control subjects and of individual metabolites in cultured urothelial cells., Subjects and Methods: Cationic fractions (CFs) were isolated from the urine specimens of 62 patients with IC and 33 control subjects by solid-phase extraction. CF metabolites were profiled using C18 reverse-phase high performance liquid chromatography (RP-HPLC) with UV detection, quantified by area-under-the-peaks using known standards, and normalized to creatinine. RP-HPLC and liquid chromatography (LC)-mass spectrometry (MS)/tandem MS (MS/MS) were used to identify major CF peaks. HTB-4 urothelial cells were used to determine the cytotoxicity of CFs and of individual metabolites with and without Tamm-Horsfall protein (THP)., Results: RP-HPLC analysis showed that metabolite quantity was twofold higher in patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was 3.1 (0.2) vs 6.3 (0.5) mAU*min/μg creatinine (P < 0.001). LC-MS identified 20 metabolites. Patients with IC had higher levels of modified nucleosides, amino acids and tryptophan derivatives compared with control subjects. The CF cytotoxicity was higher for patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was -2.3 (2.0)% vs 36.7 (2.7)% (P < 0.001). A total of 17 individual metabolites were tested for their cytotoxicity. Cytotoxicity data for major metabolites were all significant (P < 0.001): 1-methyladenosine (51%), 5-methylcytidine (36%), 1-methyl guanine (31%), N(4)-acetylcytidine (24%), N(7)-methylguanosine (20%) and L-Tryptophan (16%). These metabolites were responsible for higher toxicity in patients with IC. The toxicity of all metabolites was significantly lower in the presence of control THP (P < 0.001)., Conclusions: Major urinary cationic metabolites were characterised and found to be present in higher amounts in patients with IC compared with control subjects. The cytotoxicity of cationic metabolites in patients with IC was significantly higher than in control subjects, and control THP effectively lowered the cytotoxicity of these metabolites. These data provide new insights into toxic factor composition as well as a framework in which to develop new therapeutic strategies to sequester their harmful activity, which may help relieve the bladder symptoms associated with IC., (© 2013 The Authors. BJU International © 2013 BJU International.)

The key to successful therapy of interstitial cystitis (IC) is to correctly diagnose it. The significant majority of patients with IC have a dysfunctional bladder epithelium that allows urinary solutes (primarily potassium) to leak into the bladder wall, causing symptoms and tissue damage. Drugs that correct this dysfunction and suppress symptoms are important to achieve successful outcomes in patients. Today over 95% of females with IC are misdiagnosed as having gynecologic chronic pelvic pain, vulvodynia, vaginitis, endometriosis, overactive bladder or urinary tract infection. Men are misdiagnosed as having prostatitis. Often children are not diagnosed at all. Multimodal drug therapy may be required and can achieve successful resolution of IC in over 90% of patients. IC in children can be treated successfully with pentosan polysulfate.

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The nucleotides associated with Tamm-Horsfall protein (THP) identified in this study are 2'(3') isomers, which are uncommon and very little is known about their biochemical pathway and role in interstitial cystitis (IC). The current study provides additional evidence of our earlier finding that THP is abnormal in IC patients. This can adversely affect THP's protective function, and suggests that THP plays a role in the pathogenesis of the disease., Objective: To identify and characterise Tamm-Horsfall protein (THP)-associated metabolites present in patients with interstitial cystitis (IC). Identification of these metabolites would give us insight into the complex interaction of THP with urinary metabolites and its effect on the protective function of THP., Patients, Subjects and Methods: THP was isolated from the urine specimens of 146 patients with IC and 87 control subjects, and was analysed for total sialic acid (SA) content by 1,2-diamino-4,5-methylenedioxybenzene. 2HCl (DMB)-high performance liquid chromatography (HPLC). THP-associated metabolites were isolated by Superdex-200 size-exclusion chromatography (SEC) as a second peak (SP2) and the SP2 was further fractionated into six major components by C18 reverse phase-HPLC. Ion-pair HPLC analysis was performed to identify and quantify THP-associated metabolites. The metabolite structures were confirmed by reversed-phase HPLC combined with electrospray ionization (ESI), liquid chromatography-tandem mass spectrometry (LC-MS and LC-MS/MS) and by high-resolution ESI-time of flight mass spectrometry (HR-ESI-TOFMS)., Results: The THP-associated metabolites (SP2) were more prevalent in patients with IC than in the controls (40.4% vs 12.6%, P < 0.001) as determined by Superdex-200 SEC. Superdex-200 SEC showed higher SP2 content in patients with IC than in controls, as determined by area under the peak/100 μg of THP. The mean (sem), for patients was 84.3 (8.1) vs 18.0 (2.4) milli-absorption unit*min, for controls (P < 0.001). Total SA content of THP was much lower in SP2-positive patients with IC than those who were SP2-negative. The mean (sem) was 41.6 (3.2) vs 92.6 (2.2) nmol/mg THP, respectively (P < 0.001). Ion-pair HPLC identified SP2 metabolites as nucleotides, namely 5'-CMP, 3'-UMP, 3'-AMP, 3'-GMP, 2'-AMP and 2'-GMP. The total nucleotide content of SP2 was significantly higher in patients with IC than in controls. The mean (sem) was 25.3 (2.9) vs 2.2 (0.2) μg/mg THP, respectively (P < 0.001). LC-MS and LC-MS/MS confirmed the nucleotides based on retention time on HPLC, and mass to charge ratio (m/z) of the parent ion and the daughter ions. HR-ESI-TOFMS gave further confimation of the nucleotide sturctures with high mass accuracy., Conclusions: In the THP of patients with IC, there is a direct correlation between reduced SA levels and high prevalence of nucleotides associated with it. The THP of patients with IC has a much higher content of these nucleotides than control, and these unique nucleotide isomers identified are very consistent in all SP2-positive patients with IC, suggesting biological significance. This study provides additional evidence that THP is abnormal in patients with IC., (© 2013 BJU International.)

Introduction: It has been reported in an open-label study that the combination of alkalinized lidocaine and heparin can immediately relieve the symptoms of urinary urgency, frequency, and pain associated with interstitial cystitis (IC). This combination has also been reported to relieve pain associated with sex in patients with IC., Aim: The aim of this study was to corroborate these findings in a multicenter setting., Methods: The study design was a multicenter prospective, double-blind, crossover, placebo-controlled trial. Each participant met all of the clinical National Institute of Diabetes and Digestive and Kidney Diseases criteria (excluding cystoscopy) for IC. Each patient received drug and control, in random order, within 48 hours of enrolling in the study., Main Outcome Measures: The primary outcome measure was percent change in pain score (11-point analog pain scale) 12 hours after receiving the drug or control. Secondary measures were the global assessment response (GAR) of symptoms and 12-hour average urgency reduction determined from 11-point urgency scales., Results: Eighteen (18) patients completed the trial. The average reduction of pain over 12 hours was 21% for control and 42% for active drug (P = 0.0363). GAR was 13% for control and 50% for drug (P = 0.0137). Average urgency reduction was 13% for control and 35% for drug (P = 0.0328)., Conclusions: The combination of alkalinized lidocaine and heparin provides up to 12 hours of relief from urgency and pain associated with IC. This combination provides significant immediate relief of symptoms for patients with IC., (© 2011 International Society for Sexual Medicine.)

Purpose: We confirm the single site observation of decreased sialylation and abnormal glycosylation of Tamm-Horsfall protein in patients with interstitial cystitis compared to control subjects., Materials and Methods: Urine samples from 41 controls and 48 patients with interstitial cystitis from a total of 5 North American sites were obtained in blinded fashion as to participant status. Tamm-Horsfall protein was isolated from urine samples by salt precipitation. Protein content was determined by size exclusion chromatography and normalized to creatinine. Sialic acid was quantified by 1,2-diamino-4,5-methylene dioxybenzene (Sigma®) high performance liquid chromatography with fluorescence detection. Neutral and amino sugars were determined by high pH anion exchange chromatography with pulsed amperometric detection. N-glycans were labeled with 2-aminobenzamide and profiled using high pH anion exchange chromatography with fluorescence detection. Samples were also analyzed by matrix assisted laser desorption/ionization-time of flight mass spectrometry. Permethylated N-glycans were analyzed in the mass-to-charge ratio range of 3,000 to 6,000., Results: There was no difference in the protein-to-creatinine ratio of Tamm-Horsfall protein from patients with interstitial cystitis vs controls (49.12 vs 46.4 mg/gm, p = 0.26). Sialic acid content (67 vs 77 nmol/mg Tamm-Horsfall protein, p = 0.025) and total monosaccharide content (590.9 vs 680.6 nmol/mg Tamm-Horsfall protein, p = 0.003) were significantly decreased in patients with interstitial cystitis vs controls. Results were supported by 2-aminobenzamide N-glycan profiling and mass spectrometry, which showed a 45% decrease in a major tetra-sialylated peak (mass-to-charge ratio 4,590) in Tamm-Horsfall protein from patients with interstitial cystitis compared to controls., Conclusions: These multisite data validate that abnormal glycosylation of Tamm-Horsfall protein occurs in patients with interstitial cystitis and may have a role in interstitial cystitis causation., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The traditional diagnosis of interstitial cystitis (IC) only recognizes the severe form of the disease. The far more common early and intermittent phases of the disease are not perceived to be part of IC but rather are misdiagnosed as urinary tract infection, urethral syndrome, overactive bladder, chronic prostatitis, urethritis, or a type of gynecologic pelvic pain (such as endometriosis, vulvodynia, or some type of vaginitis). All of these patient groups actually suffer from the same bladder disease. This disease results from a leaky bladder epithelium and subsequent potassium leakage into the bladder interstitium that generates the symptoms of frequency, urgency, pain or incontinence in any combination. Robust scientific data now support this important concept. These data will be reviewed herein. The conclusions derived from these data substantially alter the paradigms for urology and gynecology in the generation of frequency, urgency and pelvic pain. All the above-mentioned syndromes unite into one primary disease process, lower urinary dysfunction epithelium, or LUDE disease, and not the 10 plus syndromes traditionally recognized., (© 2010 THE AUTHOR. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Purpose: The objective of this study was to achieve a linguistic adaptation of the original version of the Pelvic Pain and Urgency/Frequency (PUF) Patient Symptom Scale into Korean., Materials and Methods: Between June 2008 and December 2008, a linguistic adaptation was carried out by 2 native Korean speakers who were also fluent in English. First, the original English version of the PUF was translated into Korean. A panel, which included the 2 translators, reviewed the translations to form a single reconciled forward translation of the Korean version. Then, another bilingual translator, having never seen the original version, back-translated the first draft of the Korean version of the PUF into English, and this back-translation was subsequently assessed for equivalence to the original. The panel discussed all discrepancies and produced a second version. After revising the 2nd version, 10 participants [5 interstitial cystitis (IC) patients and 5 persons from the general population], stratified variously by age, sex, and educational level, answered the PUF and were systematically debriefed afterwards. A summary of the changes from the patient interviews were incorporated into the third version. After the spelling, grammar, layout, and formatting were checked, the third version was verified as the final Korean version of the PUF, without modifications., Results: The multi-step process of forward translation, reconciliation, back-translation, cognitive debriefing, and proofreading of the Korean version of the PUF was completed., Conclusions: The Korean version of the PUF scale may be helpful for screening IC patients in the Korean population and can now be used in Korea.

Introduction: Intravesical potassium sensitivity has been reported in 82% of vulvodynia patients, suggesting the bladder generates their pain and indicating interstitial cystitis (IC)/painful bladder syndrome deserves greater attention in differential diagnosis of vulvodynia., Aims: The aims of this study were to: (i) determine the prevalence of IC as detected by intravesical potassium sensitivity; and (ii) survey for urinary, pelvic pain, and sexually associated symptoms in patients with vulvodynia., Methods: Consecutive patients with vulvodynia were surveyed for urinary and pelvic pain symptoms using the pelvic pain and urgency/frequency (PUF) questionnaire, and tested for abnormal epithelial permeability using the potassium sensitivity test (PST). Rates of positive PST were determined overall and by PUF score range, and were compared in patients with intermittent vs. constant vulvodynia symptoms., Main Outcome Measures: Results of intravesical PST., Results: Of 122 vulvodynia patients, 102 (84%) had a positive PST and 97 (80%) had urologic symptoms. Of the 87 sexually active patients, 81 (93%) reported pain associated with sex. Patients with constant (72/87, 83%) vs. intermittent symptoms (30/35, 86%) had no significant difference in rates of positive PST. Mean PUF score was 13.2. PUF scores of 3-4 were associated with an 86% rate of positive PST; scores 5-9, 44%; 10-14, 84%; 15-19, 87%; 20-24, 86%; and 25 and above, 100%., Conclusion: Most patients with vulvodynia have a positive PST and urgency/frequency, indicating pain of bladder origin (IC). IC deserves far greater consideration in the differential diagnosis of patients with vulvodynia. This represents a dramatic change for the gynecologic paradigm of vulvodynia, which in many cases appears to be referred pain from the urinary bladder.

Purpose: We conducted a retrospective analysis to determine associations among symptoms, sleep disturbances and quality of life in responder and nonresponder groups of patients with interstitial cystitis., Materials and Methods: Patients in a multidose pentosan polysulfate sodium clinical trial with a diagnosis of interstitial cystitis who were randomized to 300 mg pentosan polysulfate sodium per day (128) completed the Interstitial Cystitis Symptom Index, an adapted Medical Outcomes Study Sleep scale and the Medical Outcomes Study Short Form-12 Health Survey at baseline, and at weeks 8, 16, 24 and 32. Responders were defined as those achieving a 30% or greater reduction in Interstitial Cystitis Symptom Index score from baseline to study end point (week 32 or last observation carried forward)., Results: A positive correlation at baseline was observed between sleep scores and Short Form-12 physical and mental components (r = 0.43 and 0.37, respectively, p <0.0001). Patients showed statistically significant improvement in Interstitial Cystitis Symptom Index and sleep scores by week 32. Responders (48, 43%) had a mean change in sleep score of 11.8 +/- 22.4 while nonresponders (64, 57%) had a mean change of 1.6 +/- 15.7 (p = 0.0055 between groups). The reduction in Interstitial Cystitis Symptom Index score correlated with improvement in sleep score from baseline to study end point (r = -0.33, p = 0.0003). At the study end point responders demonstrated a significant improvement in the Short Form-12 physical component compared with baseline (p <0.0001)., Conclusions: Reduction in interstitial cystitis symptoms may be associated with patient reported improvement in sleep and quality of life.

Objective: To confirm abnormal glycosylation of Tamm-Horsfall protein (THP) in patients with interstitial cystitis (IC)., Patients, Subjects and Methods: The sialic acid content of THP, a critical component of its biological activity, is reduced in patients with IC. N-glycan shows reduced levels of high molecular weight tri- and tetra-antennary sialylated oligosaccharides. These results are supported by quantitative monosaccharide analysis of neutral and amino sugars in patients vs control subjects. THP was isolated from urine samples of 23 patients with IC and 24 control subjects by salt precipitation. The sialic acid contents were measured using 1,2-diamino-4,5-methylene dioxybenzene-high performance liquid chromatography analysis. For N-glycan profiling, purified THP was treated with peptide:N-glycosidase F to release N-glycans. The purified N-glycans were labelled with 2-aminobenzamide and were profiled by high-pH anion exchange chromatography (HPAEC) with fluorescence detection. The neutral and amino sugars were determined by HPAEC with pulsed amperometric detection., Results: The total sialic acid in patients was half of that in controls. There was a pattern of reduced level of high molecular weight sialylated oligosaccharide in 17 of 23 patients vs four of 24 controls. The total neutral and amino sugars showed a approximately 30% reduction in patients. The mean (sem) for the controls was 133.79 (6.51) vs 94.76 (6.67) nmol/200 microg of THP for patients (P < 0.001)., Conclusions: THP in patients with IC has reduced sialylation and overall glycosylation, and by inference, THP has a role in the pathophysiology of IC.

Introduction: Sexual functioning is one of the strongest predictors of poorer quality of life (QOL) in patients diagnosed with interstitial cystitis/painful bladder syndrome (IC/PBS)., Aims: To examine the relationship between symptom reduction and sexual functioning in patients with IC/PBS., Methods: Patients with IC/PBS were treated with 300 mg/day pentosan polysulfate sodium for 32 weeks., Main Outcome Measures: Patients completed the O'Leary-Sant Interstitial Cystitis Symptom Index, Short Form-12 QOL, and Medical Outcomes Study Sexual Functioning Scale at baseline, and at 8, 16, 24, and 32 weeks. Treatment responders were defined as those achieving a >/=30% reduction in symptom index from baseline., Results: A total of 128 patients were included in the analyses. At baseline, mean symptom index, QOL (physical and mental), and sexual functioning scores were 12.3, 41.7, 45.9, and 56.1, respectively. Patients showed statistically significant improvement in symptom and sexual functioning scores at weeks 8, 16, 24, and 32. At week 32, the mean change in symptom index score from baseline was -2.97 (standard deviation [SD] = 4.66, P < 0.0001), and the mean change in sexual functioning score from baseline was 8.9 (SD = 32.9, P = 0.0054). Reduction in symptom index score was moderately correlated with improvement in sexual functioning score at the end of study (r = -35, P = 0.0002). Positive correlation was observed at the end of the study between the mean change scores of sexual functioning score and physical and mental QOL components (r = 0.46, P < 0.0001 and r = 0.29, P = 0.0023, respectively). Patients achieving a >/=30% reduction in symptom index (responder, N = 47; 44%) had an adjusted mean change in sexual functioning score of 19.8 (standard error [SE] = 4.69), while nonresponders (N = 59, 56%) had an adjusted mean change -0.49 (SE = 4.17) (between groups, P = 0.0020)., Conclusions: Sexual dysfunction is moderate to severe in patients with IC/PBS and impacts significantly on QOL. Reduction in symptoms was associated with improvement in the patient-reported outcomes of sexual function.

Purpose: Normal urinary Tamm-Horsfall protein shows a urothelial cytoprotective effect against potentially toxic compounds in urine that may injure the urothelium and cause bladder disease. One such disease is interstitial cystitis. In patients with interstitial cystitis this protective effect is decreased. We hypothesized that a difference in Tamm-Horsfall protein in patients with interstitial cystitis exists that may be involved in disease pathogenesis., Materials and Methods: Using enzyme-linked immunosorbent assay the urinary Tamm-Horsfall protein concentration was determined in patients with interstitial cystitis and control subjects. Sialic acid content was measured by high performance liquid chromatography based assay. The structure of the protein glycosylation chains was analyzed using matrix assisted laser desorption/ionization-time of flight mass spectrometry., Results: The mean Tamm-Horsfall protein concentration was not significantly different in patients with interstitial cystitis and controls (28.8 vs 28.2 mg/l urine and 36.8 vs 36.7 microg/mg creatinine, respectively, p = 0.6). The total mean sialic acid content of Tamm-Horsfall protein was almost 2-fold lower in 22 patients with interstitial cystitis compared with that in 20 controls (46.3 +/- 4.3 vs 75.3 +/- 4.1 nmol sialic acid per mg Tamm-Horsfall protein, respectively, p <0.0001). On matrix assisted laser desorption/ionization-time of flight mass spectrometry N-glycans released from Tamm-Horsfall protein revealed lower molecular weight di-antennary N-glycan structures and a resulting decrease in the number of terminal sialic acid residues in 10 patients with interstitial cystitis relative to those in 10 controls., Conclusions: Tamm-Horsfall protein is qualitatively different in patients with interstitial cystitis compared to controls. These data suggest that altered Tamm-Horsfall protein may be involved in interstitial cystitis pathogenesis and it may be useful for clinical diagnosis.

For the purpose of presenting a comprehensive review of current information, the medical literature was reviewed to extract data related to the clinical presentation of interstitial cystitis (IC). The most common symptoms at diagnosis are urinary urgency, daytime frequency, dysuria, pain, and nocturia. The most common sites where pain is localized are the suprapubic, pubic, vaginal, and genital areas. Pain is commonly triggered or exacerbated by vaginal intercourse in women or ejaculation in men. The most common findings on physical examination are dysphoric mood, suprapubic tenderness, and anterior vaginal wall tenderness. A voiding diary typically shows an increased number of voids per day and reduced volumes per void. Overall, published reports in the literature indicate that the clinical presentation of IC is variable. IC is readily suggested by history, physical examination, and voiding diary findings.

Emerging data are changing the pelvic pain paradigm for gynecologic patients. Historically, interstitial cystitis (IC) was rarely considered as a cause of chronic pelvic pain (CPP), but recent data suggest that IC is a common cause of CPP in gynecologic patients and perhaps is even the most common cause. It is important to consider the bladder as a generator of symptoms early in the evaluation of the gynecologic patient with CPP. New tools have been developed to aid the gynecologist in ruling out IC in patients with CPP, including a new IC symptom questionnaire and the Potassium Sensitivity Test (PST). By determining whether the pain is of bladder origin, the physician can more successfully treat the patient with CPP.

The urothelium plays a pivotal role as a barrier between urine and its solutes and the underlying bladder. Bladder surface mucus is a critical component of this function. The biologic activity of mucus that imparts this barrier function is generated by the highly anionic polysaccharide components (eg, glycosaminoglycans), which are extremely hydrophilic and trap water at the outer layer of the umbrella cell. This trapped water forms a barrier at the critical interface between urine and the bladder. The result is a highly impermeable urothelium that serves as a key protective barrier for the bladder interstitium. In interstitial cystitis (IC), disruption of the urothelial barrier may initiate a cascade of events in the bladder, leading to symptoms and disease. Specifically, epithelial dysfunction leads to the migration of urinary solutes, in particular, potassium, that depolarize nerves and muscles and cause tissue injury. Exogenous heparinoids can restore the barrier function of the urothelium and thus successfully treat patients with IC. Groups of patients who have been given a diagnosis of IC, chronic prostatitis, and urethritis have been shown to have IC by virtue of their shared potassium sensitivity. It would seem, therefore, that mucous deficiency may be present throughout the lower urinary tract. If one is to rename these diseases, perhaps it is best to do so in reference to a shared loss of epithelial barrier function. A name such as lower urinary dysfunctional epithelium would incorporate all of these diseases under a single pathophysiologic process. As a result of these discoveries, a new paradigm for diagnosis and treatment is emerging.

Objectives: Tamm-Horsfall protein (THP) from normal urine has been shown to protect against the cytotoxic effects of toxic urinary cations (TFs) in vivo and in vitro. This study investigated the effect of desialylation on the cytoprotective activity of THP., Methods: From pooled 24-hour urine specimens from healthy individuals, both TFs and THP were obtained. Sprague-Dawley rats received intravesical NaCl or KCl, and the baseline urodynamic percentage of nonvoiding contractions (NVCs) was recorded. Then, rehydrated TF, TF plus THP, or TF plus THP-desialylated (THP-d) were instilled, followed by KCl, and the urodynamic measurements were repeated. In vitro, human HTB4 bladder cells were incubated overnight with the rehydrated TF, TF plus THP, TF plus THP-d, or assay media alone, and the cytotoxicity levels were determined., Results: Acid hydrolysis resulted in an 88% loss of sialic acid. TFs consistently demonstrated a greater than 50% toxicity for human HTB4 cells compared with cells incubated in media (P <0.01). TF cytotoxic activity was blocked by preincubation with THP but not by preincubation with THP-d. Similarly, rat bladder NVCs increased significantly over baseline when KCl was infused after TF infusion (1.68 NVCs/min; P <0.0001). NVCs were significantly reduced by preincubating TFs with THP (0.42 NVCs/min) but not by preincubating with THP-d (1.55 NVCs/min, P <0.0001)., Conclusions: The cytoprotective function of urinary THP in the bladder can be compromised when a decrease is present in the sialic acid residues on THP. Such a decrease in THP cytoprotective activity may play a critical role in the pathophysiology of interstitial cystitis.

Objective: To evaluate the effects of MN-001, a novel orally active anti-inflammatory agent, in suppressing the bladder hyperactivity resulting from ovalbumin (OA)-induced mast-cell stimulation in a rat model., Materials and Methods: Sprague-Dawley rats of both sexes were divided into five groups of 10 each, with group 1 as the control and groups 2-5 undergoing OA sensitization to produce mast-cell degranulation using an established method. At 14 days after sensitization, rats were given an acute intravesical challenge: in group 1, by saline (control), and in groups 2-5, with approximately 2 mL of OA (10 mg/mL in sterile saline). Groups 3-5 received the investigational agent MN-001 orally at 10, 30 or 50 mg/kg, respectively, 1 h before intravesical OA challenge. Urodynamics were then evaluated to quantify the frequency of contractions (voids), intercontractile interval (ICI) and non-voiding contractions (NVCs)., Results: Acute intravesical OA challenge in rats in group 2 caused contractions of bladder smooth muscle, leading to a significant (P < 0.05) dose-dependent increase in NVCs and a decrease in ICI. Rats pre-treated with MN-001 at 30 and 50 mg/kg (groups 4 and 5) had significantly fewer NVCs and a greater ICI than rats in group 2 (P < 0.05)., Conclusion: OA challenge in OA-sensitized rats produces bladder hyperactivity, as reflected in significantly more NVCs and a lower ICI. At doses of 30 and 50 mg/kg orally, MN-001 produces significant protection against the OA-induced bladder hyperactivity. MN-001 might have a role in managing mast cell activity and the associated bladder symptoms in patients with interstitial cystitis.

Aim: Loss of the lower urinary permeability barrier and passive potassium cycling into tissue are an initiating event in interstitial cystitis. We tested whether a low molecular weight cytotoxic fraction from normal urine causes sensitivity to intravesical potassium in rats and whether the sulfated anionic polysaccharide pentosan polysulfate can neutralize this fraction's cytotoxic activity., Methods: A low molecular weight (> 100 < 3500) toxic urinary fraction was prepared from normal human urine by dialysis and the lyophilized, salt free product (toxic factor) further investigated. Anaesthetized adult male Sprague-Dawley rats received intravesical sodium or potassium, and urodynamic parameters, including number of voids and non-voiding contractions, were recorded. Then protamine sulfate, rehydrated toxic factor, or toxic factor plus pentosan polysulfate was infused, followed by potassium, and urodynamic measurements repeated. The toxic factor was evaluated in a commercial cytotoxicity protocol using cultured rat urothelial cells., Results: Rat bladder non-voiding contractions increased markedly over baseline when potassium was infused after toxic factor (1.681 +/- 0.1131 non-voiding contractions/min; P = 0.0004) but not after toxic factor premixed with pentosan polysulfate. Toxic factor had a significant (P < 0.001) cytotoxic effect in cultured rat bladder epithelial cells; toxic factor plus pentosan polysulfate was significantly less cytotoxic than toxic factor alone (P < 0.007)., Conclusions: Normal urine contains a cationic cytotoxic factor that increases urothelial permeability by injuring the mucosa, allowing potassium to penetrate the urothelium and depolarize the underlying nerves and muscles. Pentosan polysulfate neutralizes the toxic factor, attenuates urothelial damage, and suppresses potassium-mediated bladder hyperactivity.

Recent years have brought dramatic advances in the clinician's ability to offer effective pharmacotherapy to patients who have interstitial cystitis. Medical treatments have been developed and applied to reduce the interstitial cystitis symptoms of pelvic pain and urinary urgency/frequency, and to address underlying causes of the disorder. In addition, advances in the understanding of the natural history of interstitial cystitis have revealed that it is insidiously progressive and the classical definition--rare, severe and difficult to treat--is in fact the relatively uncommon, advanced stage of a disorder that affects most individuals in a mild-to-moderate and readily treatable form. This recognition has led to the identification of large numbers of previously unsuspected cases of interstitial cystitis, and the successful treatment of many individuals in the early stages of interstitial cystitis when it is far more responsive to therapy. A heparinoid-based multimodal medical regimen can effectively control symptoms and address disease pathophysiology in the majority of cases. Intravesical therapeutic solutions are new and promising adjunctive therapies that can offer immediate symptom relief during symptom flares, and for patients who are just beginning medical therapy.

Objectives: To test whether the presence of Tamm-Horsfall protein (THP) can limit the injury caused by low-molecular-weight (LMW) urinary cations using an in vivo rat bladder injury model. Previous studies have shown that normal urine contains LMW cations toxic to cultured bladder cells and that THP, a ubiquitous urinary glycoprotein, protects against this cytotoxic effect. THP may sequester and subsequently neutralize these toxic urinary cations., Methods: A dialysis product of LMW (greater than 100 but less than 3500) was prepared from pooled 24-hour urine samples from healthy volunteers and evaluated for urothelial cell cytotoxicity. The LMW toxic factor (TF) was instilled into the bladders of Sprague-Dawley rats (n = 9) after recording the baseline urodynamic parameters, primarily nonvoiding contractions (NVCs). We also evaluated the ability of THP to block abnormal physiologic activity indicative of bladder injury caused by exposure to the TF (greater than 100 but less than 3500 molecular weight) by co-instillation of the TF with THP., Results: The TF had a significant cytotoxic effect in cultured rat (P < 0.01) and human (P < 0.01) bladder epithelial cells. Rat bladder NVCs increased significantly over baseline contractility when potassium chloride was infused after TF (1.68 +/- 0.11 NVC/min; P < 0.0001) but not after infusion of THP plus TF (0.28 +/- 0.085 NVC/min)., Conclusions: Normal urine contains a cationic factor that appears to increase urothelial permeability by injuring the mucosa, allowing potassium ions to penetrate the urothelium and depolarize underlying nerves and muscle. THP appears to neutralize the LMW fraction electrostatically and attenuate urothelial damage, resulting in suppression of potassium chloride-mediated bladder hyperactivity.