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Background: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner's ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients' biopsies., Methods: We performed paired microRNA (miRNA) and mRNA expression profiling in the bladder biopsies of BPS patients with non-Hunner interstitial cystitis phenotype, using comprehensive Next-generation sequencing (NGS) and studied the activated pathways and altered biological processes based on the global gene expression changes. Paired mRNA-miRNA transcriptome analysis delineated the regulatory role of the dysregulated miRNAs by identifying their targets in the disease-induced pathways., Results: EIF2 Signaling and Regulation of eIF4 and p70S6K Signaling, activated in response to cellular stress, were among the most significantly regulated processes during BPS. Leukotriene Biosynthesis nociceptive pathway, important in inflammatory diseases and neuropathic pain, was also significantly activated. The biological processes identified using Gene Ontology over-representation analysis were clustered into six main functional groups: cell cycle regulation, chemotaxis of immune cells, muscle development, muscle contraction, remodeling of extracellular matrix and peripheral nervous system organization and development. Compared to the Hunner's ulcerative type IC, activation of the immune pathways was modest in non-ulcerative BPS, limited to neutrophil chemotaxis and IFN-γ-mediated signaling. We identified 62 miRNAs, regulated and abundant in BPS and show that they target the mRNAs implicated in eIF2 signalling pathway., Conclusions: The bladders of non-ulcerative BPS patients recruited in this study had alterations consistent with a strong cell proliferative response and an up-regulation of smooth muscle contractility, while the contribution of inflammatory processes was modest. Pathway analysis of the integrated mRNA-miRNA NGS dataset pinpointed important regulatory miRNAs whose dysregulation might contribute to the pathogenesis. Observed molecular changes in the peripheral nervous system organization and development indicate the potential role of local bladder innervation in the pain perceived in this type of BPS., (© 2021. The Author(s).)

New findings provide progress in the understanding of the complicated aetiopathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS), whose causalities have only been deciphered in fragments so far. An increasingly complex network of pathomechanisms is emerging, in which the frequently mentioned mast cells and urothelial changes seem to be only a fragment of the pathological changes. The latest findings regarding a possible genetic and epigenetic predisposition are based on pedigree analyses, detection of single nucleotide polymorphisms and significant changes in differentially expressed genes. Multiple alterations can be detected at the molecular level. Platelet-activating factor, VEGF, corticotropin-releasing hormone and the inflammasome are important players in understanding the disease, but the pathomechanism underlying the "activation" of IC remains unclear. New starting points could be the detection of viruses (Epstein-Barr virus, BK polyomaviruses) or bacterial inflammation by pathogens that cannot be detected in standard cultures., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Objective: To further examine anesthetic bladder capacity as a biomarker for interstitial cystitis/bladder pain syndrome (IC/BPS) patient subtypes, we evaluated demographic and clinical characteristics in a large and heterogeneous female patient cohort., Material and Methods: This is a retrospective review of data from women (n = 257) diagnosed with IC/BPS who were undergoing therapeutic bladder hydrodistention (HOD). Assessments included medical history and physical examination, validated questionnaire scores, and anesthetic BC. Linear regression analyses were computed to model the relationship between anesthetic BC and patient demographic data, symptoms, and diagnoses. Variables exhibiting suggestive correlations (P ≤ .1) were candidates for a multiple linear regression analysis and were retained if significant (P ≤ .05)., Results: Multiple regression analysis identified a positive correlation between BC and endometriosis (P = .028) as well as negative correlations between BC and both ICSI score (P < .001) and the presence of Hunner's lesions (P < .001). There were higher average numbers of pelvic pain syndrome (PPS) diagnoses (P = .006) and neurologic, autoimmune, or systemic pain (NASP) diagnoses (P = .003) in IC/BPS patients with a non-low BC, but no statistical difference in the duration of diagnosis between patients with low and non-low BC (P = .118)., Conclusion: These data, generated from a large IC/BPS patient cohort, provide additional evidence that higher BC correlates with higher numbers of non-bladder-centric syndromes while lower BC correlates more closely with bladder-specific pathology. Taken together, the results support the concept of clinical subgroups in IC/BPS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, debilitating syndrome involving bladder pain and lower urinary tract symptoms (LUTS), with a substantial effect on patients' quality of life. IC/BPS poses a diagnostic challenge, and its available treatment options remain only moderately effective. Bladder-wall biopsies from IC/BPS patients commonly uncover mastocytosis. While mast-cells are suspected as pivotal in disease pathogenesis, the clinical significance of their presence remains unclear. Clinical guidelines differ on whether or not bladder biopsies should be a part of routine IC/BPS workup., Aims: To determine whether detrusor mastocytosis can serve as a prognostic marker for treatment response and improvement duration., Methods: We retrospectively collected patient data for IC/BPS patients who underwent bladder hydrodistension under anesthesia. We used statistical modelling to determine the effect of mastocystosis and other possible predictive factors - age, comorbidity, Hunner lesions - on the presence and duration of symptom improvement., Results: A total of 35 patients (89% female, median age 63.5 [IQR 48.8-73.6] years) underwent hydrodistension, of whom 28 (89% female, median age 63.0 [44.8-73.1] years) had bladder biopsies; 11 (39%) of them had mastocystosis. Within a median follow-up of 8.8 [1.7-24.2] months, 11 (100%) of the patients with mastocytosis and 9 (53%) of the patients without it, experienced symptomatic improvement (p=0.007). Improvement duration was 8 months longer (p=0.006) in those with mastocystosis. Univariate logistic regression models were used to estimate odds ratios (OR). Mastocytosis (p=0.004) and Charlson Comorbidity score were the only variables with a statistically significant OR. Univariate survival models were fitted, and improvement duration was estimated to be longer in patients with mastocystosis (p=0.01). A multivariate Cox regression model found no variable to be statistically significant, though mastocystosis was borderline significant (p=0.055)., Conclusions: Mastocystosis defines a discernible phenotype of IC/BPS, which exhibits higher rates and longer duration of hydrodistention treatment response., Discussion: Notwithstanding limitations of sample size and retrospective study design, we were able to demonstrate that mastocystosis can serve as a prognostic factor for symptom improvement after hydrodistension in IC/BPS patients. Prospective studies are required to validate this finding and to investigate the mechanisms involved.

Interstitial cystitis (IC)/bladder pain syndrome (BPS) primarily affects women. It varies in its severity and currently has no effective treatment. The symptoms of IC include pelvic pain, urgency and frequency of urination, and discomfort or pain in the bladder and lower abdomen. The bladders of IC patients exhibit infiltration by immune cells, which lends credence to the hypothesis that immune mechanisms also play a role in the etiology and pathophysiology of IC. The Differentially expressed microRNAs (miRs) in immune cells may serve as crucial immunoregulators in the IC. Therefore, we sought to determine whether miRs might play a regulatory role in the progression and pathogenesis of IC, using experimental autoimmune cystitis (EAC) model. In the present study, we observed differential expression of a specific subset of miRs in iliac lymph nodes (ILNs) and urinary bladders (UB) of IC mice compared to that in control mice. Microarray analysis of 96 miRs from the bladder and 135 miRs from ILNs allowed us to identify 50 that exhibited at least a 1.5-fold greater difference in expression in EAC mice compared to control mice. Hierarchical cluster analysis of the microarray data was used to search available databases to predict molecular pathways with which the miRs might interact. Four miRs from each organ that exhibited altered expression in EAC mice and that were predicted to have roles in inflammation (miR-146a, -181, -1931, and -5112) were selected for further analysis by reverse transcription-polymerase chain reaction (RT-PCR). All were confirmed to be elevated in EAC mice. Histological inflammatory scores, systemic chemokines, and cytokines expressed by T helper type 1 (Th1) lymphocytes were also elevated in EAC mice as compared to control animals. We hypothesize that the mechanism of EAC induction might involve the modulation of specific miRs that increase local and systemic levels of chemokines and cytokines. The present study identifies novel miRs expressed in UB and ILNs that will allow us to highlight mechanisms of EAC pathogenesis and may provide potential biomarkers and/or serve as the basis of new therapies for the treatment of IC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kumar, Kiran, Shamran and Singh.)

Objective: To evaluate the specific contribution of ilioinguinal (II) and iliohypogastric (IH) nerve injury and referred pain to interstitial cystitis/bladder pain syndrome and patient-reported chronic pelvic pain, and to enumerate the effects of II and IH nerve resection on the pain and voiding symptoms in patients with IC/BPS., Materials and Methods: This was a prospective cohort study of 8 patients with ICS/BPS who had prior abdominal surgery. All patients received diagnostic image guided T12/L1 nerve blocks, followed by II and IH nerve resections. Validated O'Leary-Sant ICS symptom indices (OSPI) and pelvic pain and urgency/frequency patient symptoms scale (PUF) scores were collected at specified intervals pre- and post-operatively., Results: Median scores at pre-operative (OSPI 13.9, PUF 20.4) and 1 week time points (OSPI 5.9, PUF 11), as well as differences between pre-operative and 10 month time points (OSPI 3.7, PUF 6) were all statistically significant (P = .008 and .009 at 1 week, and .007 and .008 at 10 months, for OSPI and PUF respectively). The mean difference in score from pre-operative to longest follow-up as measured by the OSPI was -14.4 (P < .001) and by PUF -10.3 (P < .001). All time points registered demonstrated improvement in pain scores. There were no surgical complications or adverse events., Conclusion: II and IH nerve resection may be an effective and durable treatment option for those with prior abdominal surgery who have referred interstitial cystitis/bladder pain syndrome pain from these injured nerves., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Up to 85% of women with interstitial cystitis/bladder pain syndrome have pelvic floor dysfunction and hypertonicity. Current evaluation methodologies lack objective measures of pelvic floor muscle activity. We examined the ability of using intravaginal high-density surface electromyography to quantitatively, objectively and noninvasively map pelvic floor muscle activity and innervation zone locations in patients with interstitial cystitis/bladder pain syndrome., Materials and Methods: Fifteen women with interstitial cystitis/bladder pain syndrome and 15 controls underwent 2 sessions of digital pelvic examinations and high-density surface electromyography assessments. The root mean squared amplitude of high-density surface electromyography was first calculated, and the resting root mean squared ratio was then calculated by normalizing the resting electromyography root mean squared to the peak electromyography amplitude reached during maximum voluntary contraction. Innervation zone distributions were obtained from decomposed high-density surface electromyography signals. The correlation between the root mean squared ratio and interstitial cystitis/bladder pain syndrome symptom scores and pelvic floor muscle alignment were investigated in patients with interstitial cystitis/bladder pain syndrome and healthy controls., Results: Women with interstitial cystitis/bladder pain syndrome demonstrated significantly increased resting root mean squared ratios compared to controls (0.155±0.048 vs 0.099±0.041, p=0.0019). Significant correlations were found between resting root mean squared ratio and patient reported pain (r s =0.523, p=0.003), interstitial cystitis symptom (r s =0.521, p=0.003) and problem indices (r s =0.60, p <0.001). In addition, women with interstitial cystitis/bladder pain syndrome were more likely to have shortened pelvic floor muscles (80%, 12 vs 13.3%, 2, p <0.01). Women with shortened pelvic floor muscles demonstrated significantly higher resting root mean squared ratio compared to those with normal pelvic floor muscle length (0.155±0.046 vs 0.107±0.040, p=0.0058)., Conclusions: Intravaginal high-density surface electromyography offers an objective and quantitative strategy to noninvasively assess pelvic floor muscle dysfunction in women with interstitial cystitis/bladder pain syndrome. Abundant spatiotemporal muscle activity information captured by high-density surface electromyography allows for mapping innervation zone distributions for major pelvic floor muscles.

The current trends in understanding the pathogenesis of infectious and inflammatory urogenital disorders are highlighted in the review. The etiological and pathogenetic significance of increased intestinal permeability for pathogens in the development of various diseases has been convincedly proved. There is no doubt about the pathogenetic role of increased permeability of the bladder mucosa, which can result in interstitial cystitis (IC). The association of intestinal diseases with IC has been established. In rats, the induction of intestinal inflammation may cause increased permeability of the bladder mucosa. In the postoperative period, bacteria are translocated from the gastrointestinal tract to the urinary tract, which is associated with stress. Particular attention is paid to the therapy based on new knowledge about the pathogenesis of infectious and inflammatory diseases of the urogenital tract. Possibilities of decreasing intestinal and bladder permeability using rebamipide are described. Various therapeutic mechanisms of action made it possible to use this drug in endoscopy, ophthalmology, chemotherapy and rheumatology. The antioxidant and anti-inflammatory properties of rebamipide has been shown in-vitro. Intravesical instillation of rebamipide accelerates the recovery of damaged urothelium and its barrier function, and also influences on bladder hyperactivity. Thus, the first results of using rebamipide in urology are encouraging; however, further researches are required.

Background: To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients., Methods: We assessed flare status every 2 weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain 1-year longitudinal study. Flare symptoms, flare start date, and exposures in the 3 days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected nonflare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants' first 3 zip code digits. Values in the 3 days before and the day of a flare, as well as changes in these values, were compared to nonflare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population., Results: A total of 574 flare and 792 nonflare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5389 nonflare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season., Conclusions: We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients is susceptible., (© 2020 Wiley Periodicals, Inc.)

Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition., (© 2020 The Japanese Urological Association.)

HMGB1, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin α capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.

The purpose of this study was to reduce the amount of stem cells used in treating preclinical interstitial cystitis (IC model) by investigating the synergistic effects of multipotent mesenchymal stem cells (M-MSCs; human embryonic stem cell-derived) and N-acetylcysteine (NAC). Eight-week-old female Sprague-Dawley rats were divided into seven groups, i.e., sham ( n = 10), lipopolysaccharide/protamine sulfate (LPS/PS; n = 10), LPS/PS + NAC ( n = 10), LPS/PS with 25K MSC ( n = 10), LPS/PS with 50K MSC ( n = 10) LPS/PS + 25K MSC + NAC ( n = 10), and LPS/PS + 50K MSC + NAC ( n = 10). To induce the IC rat model, protamine sulfate (10 mg, 45 min) and LPS (750 μg, 30 min) were instilled once a week for five consecutive weeks via a transurethral PE-50 catheter. Phosphate-buffered saline (PBS) was used in the sham group. One week after the final instillation, M-MSCs with two suboptimal dosages (i.e., 2.5 or 5.0 × 10 4 cells) were directly transplanted into the outer-layer of the bladder. Simultaneously, 200 mg/kg of NAC or PBS was intraperitoneally injected daily for five days. The therapeutic outcome was evaluated one week after M-MSC or PBS injection by awake cystometry and histological analysis. Functionally, LPS/PS insult led to irregular micturition, decreased intercontraction intervals, and decreased micturition volume. Both monotherapy and combination therapy significantly increased contraction intervals, increased urination volume, and reduced the residual volume, thereby improving the urination parameters compared to those of the LPS group. In particular, a combination of NAC dramatically reduced the amount of M-MSCs used for significant restoration in histological damage, including inflammation and apoptosis. Both M-MSCs and NAC-based therapy had a beneficial effect on improving voiding dysfunction, regenerating denudated urothelium, and relieving tissue inflammation in the LPS-induced IC/BPS rat model. The combination of M-MSC and NAC was superior to MSC or NAC monotherapy, with therapeutic efficacy that was comparable to that of previously optimized cell dosage (1000K) without compromised therapeutic efficacy.

Stress is associated with exacerbated symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). To investigate the mechanism of stress implicated on IC/BPS, we investigated expression of stress-response receptor corticotropin-releasing hormone receptor (CRHR) in bladder from IC/BPS patients. Twenty-three IC/BPS patients with Hunner's lesion (HIC), 51 IC/BPS patients without Hunner's lesion (NHIC), and 24 patients with stress urinary incontinence as controls were enrolled. Cystoscopic biopsies of bladder wall including mucosa and submucosa were obtained from all patients. Western blotting was used to investigate the bladder expression of the CRHR1 and CRHR2. Immunochemical staining revealed CRHR1 expression was mainly located in the submucosa while CRHR2 expression was mainly in uroepithelial cells. Compared to control subjects, the CRHR1 expression was significantly higher, while CRHR2 expression was significantly lower in IC/BPS patients. Further analysis of patients with HIC, NHIC, and control subjects showed that bladder in patients with HIC had significantly higher expressions of CRHR1 and significantly lower CRHR2. CRHR2 expression was significantly negatively correlated with O'Leary-Sant score and bladder pain. Our results indicate dysregulation of bladder CRHR1 and CRHR2 in patients with IC/BPS, and suggest CRH signaling may be associated with IC/BPS symptoms.

To investigate the risks of overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC) in primary Sjögren's syndrome (pSS) patients. A nationwide, population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database. From 2001 to 2010, participants with newly diagnosed pSS were recognized as the study group. In addition, a comparison cohort of non-pSS participants was matched for age, gender, and initial diagnosis date. Risks of developing OAB and BPS/IC in pSS patients of different age, sex, and various therapeutic strategies were calculated. Hazard ratios (HR) and a 95% confidence interval (CI) were analyzed by Cox proportional hazard model. In total, 11,526 pSS patients were recognized. The HRs of OAB and BPS/IC in pSS patients were 1.68 (95% C.I.: 1.48-1.91, p<0.01) and 2.34 (95% C.I.: 1.59-3.44, p<0.01), respectively. The risks of OAB and BPS/IC were significantly increased for pSS patients aged < 65 years (HR: 1.73 and 2.67), female patients (HR: 1.74 and 2.34), and patients requiring treatment for dry eyes and dry mouth (HR: 2.06 and 2.93). pSS patients exhibited an increased risk of OAB and BPS/IC. Female gender, younger age, and severe glandular dysfunction requiring treatments were potential risk factors., Competing Interests: The authors have declared that no competing interests exist.

Introduction and Hypothesis: Interstitial cystitis (IC) and bladder pain syndrome (BPS) are challenging and encompassing hypersensitivity disorders of the lower urinary tract. A variety of national and international guidelines have been published including guidance on nomenclature, definitions, etiopathology, diagnostics and treatment. A lack of universally established clinical guidance is apparent. The aim of this review is to evaluate key guidelines on this area of practice, identify variations, compare their recommendations and grade them using AGREE II., Methods: Literature searches were performed using the PUBMED and CINAHL database from January 1, 1983, to December 1, 2018, referring to the search strategy of AUA. Ten national and international guidelines were included into the analysis. We assessed the guidelines with the updated AGREE II., Results: Symptoms congruent in all guidelines are: pain, pressure, discomfort and frequency, urgency and nocturia. Urinalysis is a prerequisite for diagnostics, cystoscopy for most and urodynamics not part of the routine assessment. Treatment options are recommended stepwise. The highest level of evidence and consensus was identified for oral therapies. Nine guidelines had an overall quality score ≥ 50% and three scored ≥ 70% (AUA, GG, RCOG)., Conclusions: The guidelines are congruent in symptom reporting, quite congruent in diagnostics and vary to a high degree on treatment recommendations. The complexity of BPS and emerging evidence indicate the need for regular updating of the guidelines and a wider consensus.

Introduction and Hypothesis: Interstitial cystitis/bladder pain syndrome (IC/BPS) and fibromyalgia (FM) are frequently co-occurring medical diagnoses in patients referred to the urology clinic for secondary and tertiary treatment options., Methods: Abundant literature has shown that many patients with FM have small fiber polyneuropathy (SFPN) that can be confirmed via skin punch biopsy and immunological staining to measure nerve density., Results and Conclusions: This finding of SFPN provides a therapeutic target for FM and in this article we hypothesize and provide rationale for the idea that this same phenomenon (SFPN) might explain, in some IC/BPS patients, the finding of widespread pain and likewise provide a therapeutic target for these patients.

A significant workforce shortage of urologists available to serve the US population has been projected to occur over the next decade. Accordingly, much of the management of urologic patients will need to be assumed by other specialties and practitioners. Since primary care physicians are often first evaluate common urologic complaints, it makes sense that these physicians are in an excellent position to intervene in the management of these patients when appropriate. One of the most common complaints in urology is voiding dysfunction. The incidence of voiding dysfunction increases with age, with conservative estimates showing that over 50% of elderly patients suffer. Despite this high prevalence and its negative impact on quality of life, however, few seek or receive treatment, as many do not readily disclose these impactful yet personal symptoms. We sought to summarize the typical presentation, evaluation, assessment and therapeutic options for both male and female patients presenting with voiding dysfunction.

Aim: Bladder pain syndrome (BPS) is a complex disease which causes cognitive, behavioral, sexual, and emotional problems. Vascular factors related to bladder blood supply may be one of the etiologic cause of BPS. This study aims to investigate the bladder blood flow and internal iliac artery resistive indices of patients with BPS., Methods: A total of 30 female patients with the diagnosis of BPS and 30 female as control group were enrolled in the study. Bilateral internal iliac arterial blood flow distal to uterine arteries were examined as the primary source of vesical arterial blood supply. Peak systolic velocities, end diastolic velocities, resistive indices, and flow volumes of internal iliac arteries were measured by color Doppler ultrasonography in a single-blind fashion., Results: The blood flows volume of the right and left internal iliac arteries during empty and full bladder were significantly lower at BPS group compared with control (P < 0.05). Although the difference was not significant, the mean resistive index of right and left internal iliac arteries were lower at the control group ( P > 0.05). Aging decreased the bladder blood volume and both BPS and control group internal iliac artery blood volume decreased by aging. The decrease was more significant at the control group, but the internal iliac artery blood volume was still lower at patients with BPS compared with the control group., Conclusion: Arterial blood flow of bladder was lower at patients with BPS compared with the control group. The decrease in the vascular supply of bladder might be one of the related factors for the BPS etiology., (© 2019 Wiley Periodicals, Inc.)

Objective: To document patient-reported interstitial cystitis/bladder pain syndrome (IC/BPS) flare management strategies and triggers., Materials and Methods: Twenty-four male and 29 female participants enrolled at the Washington University site of the MAPP Research Network completed a questionnaire on strategies they utilized to manage flares and factors they believed triggered their flares (eg, specific food items, physical activities, sexual activities, infections, and stress). Participants were also asked about the diurnal timing of their flares., Results: A total of 96.2% of participants reported having ever experienced a symptom flare. Participants treated or managed their flares using a wide variety of strategies, ranging from common strategies, such as drinking additional water or fluid (74.5%), to less common strategies, such as acupuncture/acupressure (5.9% of participants). Participants also reported a wide range of perceived flare triggers, including previously reported factors (citrus fruits, tomatoes, spicy food, alcoholic and caffeinated beverages, driving/sitting in forms of transportation, urinary tract infections, stress, and tight clothing), as well as some less common, previously undocumented factors (eg, certain foods, nongenitourinary infections, wearing high-heeled shoes/boots or perfume, hair dye, and toothpaste). In general, female participants and those with somatic sensory hypersensitivity reported greater numbers of therapies and triggers. Finally, flares were reported most commonly in the afternoon or evening., Conclusion: IC/BPS participants reported diverse flare management strategies and numerous perceived triggers. These findings, together with those from the small body of literature to date, provide a wide array of candidates and hypotheses for future global and tailored flare management and prevention interventions., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To investigate whether urinary levels of macrophage migration inhibitory factor (MIF) are elevated in interstitial cystitis/bladder pain syndrome (IC/BPS) patients with Hunner lesions and also whether urine MIF is elevated in other forms of inflammatory cystitis., Methods: Urine samples were assayed for MIF by enzyme-linked immunosorbent assay. Urine samples from 3 female groups were examined: IC/BPS patients without (N = 55) and with Hunner lesions (N = 43), and non-IC/BPS patients (N = 100; control group; no history of IC/BPS; cancer or recent bacterial cystitis). Urine samples from 3 male groups were examined: patients with bacterial cystitis (N = 50), radiation cystitis (N = 18) and noncystitis patients (N = 119; control group; negative for bacterial cystitis)., Results: Urine MIF (mean MIF pg/mL ±  standard error of the mean) was increased in female IC/BPS patients with Hunner lesions (2159 ± 435.3) compared with IC/BPS patients without Hunner lesions (460 ± 114.5) or non-IC/BPS patients (414 ± 47.6). Receiver operating curve analyses showed that urine MIF levels discriminated between the 2 IC groups (area under the curve = 72%; confidence interval 61%-82%). Male patients with bacterial and radiation cystitis had elevated urine MIF levels (2839 ± 757.1 and 4404 ± 1548.1, respectively) compared with noncystitis patients (681 ± 75.2)., Conclusion: Urine MIF is elevated in IC/BPS patients with Hunner lesions and also in patients with other bladder inflammatory and painful conditions. MIF may also serve as a noninvasive biomarker to select IC/BPS patients more accurately for endoscopic evaluation and possible anti-inflammatory treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To test in an animal model the hypothesis that recombinant human proteoglycan 4 (rhPRG4; lubricin), a highly O-glycosylated mucin-like glycoprotein, may be a novel surface-active therapeutic for treating bladder permeability with comorbid bowel permeability. Previously we showed that inducing bladder permeability in rats with dilute protamine sulfate (PS) produced colonic permeability and visceral hypersensitivity, suggesting increased bladder permeability could represent an etiologic factor in both interstitial cystitis-bladder pain syndrome and irritable bowel syndrome., Methods: We used an animal model of catheterized ovariectomized female rats instilled intravesically with 1 mg/mL PS for 10 minutes that after 24 hours were treated with 1.2 mg/mL lubricin or with vehicle alone. After 24 hours the bladder and colon were removed and permeability assessed electrophysiologically with the Ussing chamber to measure the transepithelial electrical resistance. A second set of rats was treated identically, except permeability was assessed on day 3 and on day 5 using contrast-enhanced magnetic resonance imaging with gadolinium diethylenetriamine penta-acetic acid instilled into the bladder., Results: Intravesical lubricin reversed bladder permeability induced by PS and prevented the concomitant increase in permeability induced in the bowel (organ crosstalk). The protective effect was confirmed with magnetic resonance imaging, and because individual rats could be followed over time, the impermeability of the bladder restored by rhPRG4 remained for 5 days., Conclusion: These data indicate that instillation of rhPRG4 into a permeable bladder can restore its normally impermeable state, and that the effect lasts for 5 days and also prevents bowel symptoms often comorbid with interstitial cystitis-bladder pain syndrome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Previous studies have suggested an association between bladder pain syndrome/interstitial cystitis (BPS/IC) and endometriosis. However, no nation-wide population study has yet reported an association between them. In this study, we examined the risk of BPS/IC among subjects with endometriosis during a 3-year follow-up in Taiwan using a population-based dataset., Study Design: This study comprised 9191 subjects with endometriosis, and 27 573 subjects randomly selected as controls. We individually followed-up each subject (n = 36 764) for a 3-year period to identify subjects subsequently diagnosed with BPS/IC. A Cox proportional hazards regression model was employed to estimate the risk of subsequent BPS/IC following a diagnosis of endometriosis., Results: Incidences of BPS/IC during the 3-year follow-up period was 0.2% and 0.05% for subjects with and without endometriosis, respectively. The hazard ratio for developing BPS/IC over a 3-year period for subjects with endometriosis compared to subjects without endometriosis was 4.43 (95% CI: 2.13-9.23). After adjusting for co-morbidities like diabetes, hypertension, coronary heart disease, obesity, hyperlipidemia, chronic pelvic pain, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, depression, panic disorder, migraines, sicca syndrome, allergies, endometriosis, asthma, tobacco use, and alcohol abuse, the Cox proportional hazards regressions revealed that the hazard ratio for BPS/IC among subjects with endometriosis was 3.74 (95% CI = 1.76-7.94, P < 0.001) compared to that in controls., Conclusions: This study provides epidemiological evidence of an association between endometriosis and a subsequent diagnosis of BPS/IC., (© 2017 Wiley Periodicals, Inc.)

Interstitial cystitis is an exceptional entity during primary Sjögren's syndrome. In this regard, we report the case of a 67-year-old patient in whom initially idiopathic interstitial cystitis revealed primary Sjögren's syndrome after 5 years of evolution in front of xerostomiaa, xerophtalmia and bilateral parotid hypertrophy with histological confirmation at the biopsy of accessory salivary glands.

The exact pathophysiology of interstitial cystitis/painful bladder syndrome is unknown; however, autoimmunity is a valid theory. We developed an autoimmune chronic cystitis model by administration of the medium dose of immunogenic peptide T2. Sixty female C57BL/6 mice were divided into six groups. The control group was not treated with any reagent. CFA group was injected with CFA + normal saline, homogenate group with bladder homogenate + CFA, low-dose group with low dose of T2 peptide + CFA, medium dose group with the medium dose of T2 peptide + CFA, and high-dose group with the high dose of T2 peptide + CFA. Micturition habits, withdrawal frequencies of mice, and bladders weight were measured for each group. Hematoxylin and eosin staining and toluidine blue staining were used to investigate bladder inflammation and mast cells accumulation, respectively. T cells infiltration in the bladder tissues and serum TNF-α level were measured by using immunohistochemistry and ELISA, respectively. Mice immunized with the medium dose of T2 peptide (0.225 mg/ml) were extremely sensitive to the applied force, showed greater urine frequencies, and higher bladder weights. Histologic examination revealed severe edema and inflammation in bladder tissues of medium-dose group. Extensive infiltration of T cells in bladder tissues, elevated TNF-α, and increased mast cells accumulation were observed in medium-dose group as compared to that in other groups. EAC mice model established by injecting the medium dose of T2 (0.225 mg/ml) mimics all the symptoms and pathophysiologic characteristics of IC/PBS. We believe that this model can help us to investigate the pathogenesis of IC/PBS.

Interstitial cystitis/bladder pain syndrome, recurrent urinary tract infections and other forms of cystitis significantly impact the quality of life of patients with chronic bladder disorders and impose a considerable economic burden on health systems. Effective management is essential to provide symptom relief and to reduce the negative impact of chronic bladder disorders. Identifying the appropriate pharmacological or non-pharmacological approach is essential, and there is a growing evidence base for the use of intravesical hyaluronic acid and chondroitin sulfate in several bladder conditions, including recurrent urinary tract infections.

Sjogren's syndrome (SS) is the 2nd most common chronic autoimmune rheumatic disease and associated with a high burden of illness. Morbidity arises not only from untreated xerostomia and keratoconjunctivitis sicca but also from extra-glandular manifestations including the development of non-Hodgkin's B cell lymphomas. Proper diagnosis of SS requires objective evidence of dry eyes and/or objective evidence of dry mouth as well as proof of autoimmunity. The recent development of new international classification criteria and clinical practice guidelines for SS should not only enhance the existing standards of care but also facilitate further studies to improve future diagnosis and outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease characterized by severe pelvic pain and urinary frequency. Mesenchymal stem cell (MSC) therapy is a promising approach to treat incurable IC/BPS. Here, we show greater therapeutic efficacy of human embryonic stem cell (hESC)-derived multipotent stem cells (M-MSCs) than adult bone-marrow (BM)-derived counterparts for treating IC/BPS and also monitor long-term safety and in vivo properties of transplanted M-MSCs in living animals. Controlled hESC differentiation and isolation procedures resulted in pure M-MSCs displaying typical MSC behavior. In a hydrochloric-acid instillation-induced IC/BPS animal model, a single local injection of M-MSCs ameliorated bladder symptoms of IC/BPS with superior efficacy compared to BM-derived MSCs in ameliorating bladder voiding function and histological injuries including urothelium denudation, mast-cell infiltration, tissue fibrosis, apoptosis, and visceral hypersensitivity. Little adverse outcomes such as abnormal growth, tumorigenesis, or immune-mediated transplant rejection were observed over 12-months post-injection. Intravital confocal fluorescence imaging tracked the persistence of the transplanted cells over 6-months in living animals. The infused M-MSCs differentiated into multiple cell types and gradually integrated into vascular-like structures. The present study provides the first evidence for improved therapeutic efficacy, long-term safety, and in vivo distribution and cellular properties of hESC derivatives in preclinical models of IC/BPS.

Purpose: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic pain syndrome and a chronic inflammatory condition prevalent in women that leads to urgency, sleep disruption, nocturia and pain in the pelvic area, to the detriment of the sufferer's quality of life. The aim of this review is to highlight the newest diagnostic strategies and potential therapeutic techniques., Methods: A comprehensive literature review was performed on MEDLINE, PubMed, and Cochrane databases gathering all literature about "Interstitial cystitis" and "Painful Bladder Syndrome". Visual analogue scales, epidemiological strategies, pain questionnaires and similar techniques were not included in this literature survey., Results: The etiology, exact diagnosis and epidemiology of IC/PBS are still not clearly understood. To date, its prevalence is estimated to be in the range of 45 per 100,000 women and 8 per 100,000 men, whereas joint prevalence in both sexes is 10.6 cases per 100,000. There are no "gold standards" in the diagnosis or detection of IC/PBS, therefore, several etiological theories were investigated, such as permeability, glycosaminoglycans, mast cell, infection and neuroendocrine theory to find new diagnostic strategies and potential biomarkers., Conclusion: Due to the fact that this disease is of an intricate nature, and that many of its symptoms overlap with other concomitant diseases, it could be suggested to classify the patients with emphasis on the phenotype, as well as their symptom clusters, to tailor the diagnostic and management choices according to the observed biomarkers.

Background: Interstitial cystitis (IC) is a chronic inflammation disorder mainly within the submucosal and muscular layers of the bladder. As the cause of IC remains unknown, no effective treatments are currently available. Administration of stem cell provides a potential for treatment of IC., Methods: This study was conducted using urine-derived stem cells (USCs) for protamine/lipopolysaccharide (PS/LPS)-induced interstitial cystitis in a rodent model. In total, 60 female Sprague-Dawley rats were randomized into three experimental groups (n = 5/group): sham controls; IC model alone; and IC animals intravenously treated with USCs (1.2 × 10 6 suspended in 0.2 ml phosphate-buffered saline (PBS)., Results: Our data showed that the bladder micturition function was significantly improved in IC animals intravenously treated with USCs compared to those in the IC model alone group. The amount of antioxidants and antiapoptotic protein biomarkers heme oxygenase (HO)-1, NAD(P)H quinine oxidoreductase (NQO)-1, and Bcl-2 within the bladder tissues were significantly higher in IC animals intravenously treated with USCs and lower in the sham controls group as assessed by Western blot and immunofluorescent staining. In addition, the expression of autophagy-related protein LC3A was significantly higher in the IC model alone group than that in IC animals intravenously treated with USCs. Inflammatory biomarkers and apoptotic biomarkers (interleukin (IL)-6, tumor necrosis factor (TNF)α, nuclear factor (NF)-κB, caspase 3, and Bax) and the downstream inflammatory and oxidative stress biomarkers (endoplasmic reticulum stress and autophagy-related protein (GRP78, LC3, Beclin1)) in the bladder tissue revealed statistically different results between groups., Conclusions: USCs restored the bladder function and histological construction via suppressing oxidative stress, inflammatory reaction, and apoptotic processes in a PS/LPS-induced IC rodent model, which provides potential for treatment of patients with IC.

Over the past two decades, there has been lot of interest in the use of liposomes as lipid-based biocompatible carriers for drugs administered by the intravesical route. The lipidic bilayer structure of liposomes facilitates their adherence to the apical membrane surface of luminal cells in the bladder, and their vesicular shape allows them to co-opt the endocytosis machinery for bladder uptake after instillation. Liposomes have been shown to enhance the penetration of both water-soluble and insoluble drugs, toxins, and oligonucleotides across the bladder epithelium. Empty liposomes composed entirely of the endogenous phospholipid, sphingomyelin, could counter mucosal inflammation and promote wound healing in patients suffering from interstitial cystitis. Recent clinical studies have tested multilamellar liposomes composed entirely of sphingomyelin as a novel intravesical therapy for interstitial cystitis. In addition, liposomes have been used as a delivery platform for the instillation of botulinum toxin in overactive bladder patients. The present review discusses the properties of liposomes that are important for their intrinsic therapeutic effect, summarizes the recently completed clinical studies with intravesical liposomes and covers the latest developments in this field., (© 2017 The Japanese Urological Association.)

Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell-deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis-induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Pelvic organ cross sensitization is considered to contribute to overlapping symptoms in chronic pelvic pain syndrome. Nerve growth factor over expression in the bladder is reportedly involved in the symptom development of bladder pain syndrome/interstitial cystitis. We examined whether a reduction of over expressed nerve growth factor in the bladder by intravesical treatment with liposome and oligonucleotide conjugates would ameliorate bladder hypersensitivity in a rat colitis model., Materials and Methods: Adult female rats were divided into 1) a control group, 2) a colitis-oligonucleotide group with intracolonic TNBS (2,4,6-trinitrobenzene sulfonic acid) enema and intravesical liposome-oligonucleotide treatments, 2) a colitis-saline group with intracolonic TNBS and intravesical saline treatments, 4) a sham oligonucleotide group with intravesical liposome-oligonucleotide treatment without colitis and 5) a sham-saline group with intravesical saline treatment without colitis. Liposomes conjugated with nerve growth factor antisense oligonucleotide or saline solution were instilled in the bladder and 24 hours later colitis was induced by TNBS enema. Effects of nerve growth factor antisense treatment were evaluated by pain behavior, cystometry, molecular analyses and immunohistochemistry 10 days after TNBS treatment., Results: In colitis-oligonucleotide rats nerve growth factor antisense treatment ameliorated pain behavior and decreased a reduction in the intercontraction interval in response to acetic acid stimulation as well as nerve growth factor expression in the bladder mucosa. All were enhanced in colitis-saline rats compared to sham rats., Conclusions: Nerve growth factor over expression in the bladder mucosa and bladder hypersensitivity induced after colitis were decreased by intravesical application of liposome-oligonucleotide targeting nerve growth factor. This suggests that local antinerve growth factor therapy could be effective treatment of bladder symptoms in chronic pelvic pain syndrome., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a syndrome of unpleasant bladder sensations and lower urinary tract symptoms. The three main proposed etiologies are bladder urothelial dysfunction, bladder inflammation (possible neurogenic), and neuropathic pain. Despite decades of basic and clinical research, IC/BPS remains difficult to treat. A variety of treatments are used, each aimed towards one etiology. For example, glycosaminoglycans are thought to improve the urothelial permeability barrier, anti-inflammatory agents are used to decrease general inflammation, and mast cell stabilizers and/or antagonists of mast cell products are used in the treatment of neurogenic inflammation. In the (unfortunately frequent) event that a treatment fails, possible reasons are that (1) the clinician is aiming towards the wrong etiology for that patient (i.e., the treatment is off target) or (2) the correct etiology is being targeted, but the treatment is not ameliorating it (i.e., the treatment is sub-therapeutic). This is a crucial distinction, because an off-target treatment should be abandoned, but a sub-therapeutic treatment should be escalated. Currently, our inability to make this crucial distinction is the greatest obstacle to effective treatment. An important future advance would be to identify urine or serum biomarkers specific to each etiologic target. Then, each biomarker could be used to select appropriate patients for each treatment and monitor the treatment's effect on its intended target.

Pelvic inflammatory disease (PID) has been investigated in Western countries and identified to be associated with chronic pelvic pain and inflammation. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a complex syndrome that is significantly more prevalent in women than in men. Chronic pelvic pain is a main symptom of BPS/IC, and chronic inflammation is a major etiology of BPS/IC. This study aimed to investigate the correlation between BPS/IC and PID using a population-based dataset.We constructed a case-control study from the Taiwan National Health Insurance program. The case cohort comprised 449 patients with BPS/IC, and 1796 randomly selected subjects (about 1:4 matching) were used as controls. A Multivariate logistic regression model was constructed to estimate the association between BPS/IC and PID.Of the 2245 sampled subjects, a significant difference was observed in the prevalence of PID between BPS/IC cases and controls (41.7% vs 15.4%, P < 0.001). Multivariate logistic regression analysis revealed that the odds ratio (OR) for PID among cases was 3.69 (95% confidence interval [CI]: 2.89-4.71). Furthermore, the ORs for PID among BPS/IC cases were 4.52 (95% CI: 2.55-8.01), 4.31 (95% CI: 2.91-6.38), 3.00 (95% CI: 1.82-4.94), and 5.35 (95% CI: 1.88-15.20) in the <35, 35-49, 50-64, and >65 years age groups, respectively, after adjusting for geographic region, irritable bowel syndrome, and hypertension. Joint effect was also noted, specifically when patients had both PID and irritable bowel disease with OR of 10.5 (95% CI: 4.88-22.50).This study demonstrated a correlation between PID and BPS/IC. Clinicians treating women with PID should be alert to BPS/IC-related symptoms in the population.

Interstitial cystitis/bladder pain syndrome (BPS) is still an etiologically poorly understood chronic pain syndrome. BPS is a clinical diagnosis. The current treatment modalities are aimed at symptom relief because no cure is possible. Analgesics may be used at any point in treatment but preferably for short-term relief for flares or bladder pain. AUA has issued clinical practice guidelines with a stepwise approach. The first-line therapy begins with self-care and behavior modification. Physical therapy and oral medications such as amitriptyline, PPS, or antihistamines belong to the second-line therapy. Third-line therapy requires cystoscopy and hydrodistension, treatment of Hunner lesions, or intravesical use of e.g. DMSO. Neuromodulation is considered a fourth-line therapy in patients who have failed third-line treatments. Fifth-line therapies consist of intravesical injection of BoNT or oral cyclosporin A. Cystectomy is the sixth-line therapy and the treatment of last resort.

Objectives: To characterize the interstitial cystitis (IC) associated with Sjögren's syndrome (SS)., Methods: Report of three new cases. Only cases fulfilling the American-European consensus criteria for SS and the European Society for the Study of Interstitial Cystitis criteria with positive histological findings for IC were included., Results: Thirteen cases of SS and IC have been reported in women, including the three reported here, with a mean age of 54 years. SS appeared first in 77% (n=10) of cases, a mean of 6.6 years before IC. The symptoms of IC included pollakiuria (n=11), lower abdominal pain (n=8), urinary urgency (n=5), painful micturition (n=6), hematuria (n=3) and dysuria (n=3). Urinary dilatation occurred in three cases, leading to acute renal failure in two patients. The diagnosis of IC was confirmed by anatomical evidence of cystitis inflammation on bladder biopsy in all (n=13) patients. Treatment was reported for nine patients, seven of whom (78%) received corticosteroid treatment, which was partially or completely effective in six cases. Immunosuppressive treatment was added in three cases (cyclosporine, n=2; azathioprine, n=1; cyclophosphamide, n=1). Local bladder treatments were performed, with hydraulic distension in five cases and DMSO instillation in one patient. A urinary catheter was inserted in the two cases of acute obstructive renal failure., Conclusions: Urinary symptoms without infection should lead the physician to consider a diagnosis of IC in SS patients. Urinary dilatation may occur, leading to acute obstructive renal failure. Corticosteroid treatment may be effective and local treatments have been tried., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

The intention of this article is to present a brief overview of the etiology, diagnosis, and treatment modalities of interstitial cystitis for primary care clinicians. While very succinct, it encapsulates the condition with clear and precise definition.

A 62-year-old man, who was refractory to repeated hydrodistentions for interstitial cystitis, underwent augmentation cystoplasty using ileal patch. Pathological examination revealed no malignancy. Computed tomography (CT) scan showed multiple pelvic and para-aortic lymph-node swellings at 14 months after the operation. CT-guided lymph-nodes biopsies and transurethral bladder biopsies revealed invasive urothelial carcinoma with lymph node metastasis. In patients with symptoms of interstitial cystitis, bladder cancer should be kept in mind despite negative findings of cytology and bladder biopsies.

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.)

Interstitial cystitis or bladder pain syndrome (BPS) is often a chronic debilitating condition characterised by predominantly storage symptoms and associated frequently with pelvic pain that varies with bladder filling. The aetiology is uncertain as the condition occurs in the absence of a urinary tract infection or other obvious pathology. Resulting discomfort may vary and ranges from abdominal tenderness to intense bladder spasms. Diagnosis and management of this syndrome may be difficult and is often made by its typical cystoscopic features. This review discusses the diagnosis and management of interstitial cystitis according to the current available best evidence and advises a multimodal approach in its management.

Objectives: To evaluate the impact of urinary symptoms of Painful Bladder/Pelvic Pain Syndrome and Radiation Cystitis (PBCPPS) on the Quality of Life, and self-esteem of the patient., Material and Methods: An observational, multicenter, epidemiological and cross-sectional study was performed on patients with Painful Bladder/Chronic Pelvic Pain Syndrome and Radiation Cystitis. Data was recorded on severity of urinary symptoms and QoL impairment using the PUF Score. The patients evaluated the QoL deterioration grade through the King's Health Questionnaire (KHQ), and the level of their anxiety and self-esteem with the Goldberg's Anxiety Scale (GAS) and Rosenberg's Self-Esteem Scale (RSES), respectively. Post-hoc comparisons were performed between the results of the KHQ of this study and a sample of patients with urinary incontinence (UI). Results on RSES were analyzed with data from the general population and from patients with erectile dysfunction., Results: A total of 530 cases, mostly female patients, who had been diagnosed with PBCPPS, were analyzed. High levels of deterioration in QoL were described: KHQ scores were significantly higher when compared with patients with UI (P<.01). Involvement of self-esteem was higher in patients with RC and men, who obtained scores similar to those of patients with erectile dysfunction., Conclusions: Patients with Painful Bladder Syndrome/Chronic Pelvic Pain Syndrome and Radiation Cystitis present high levels of anxiety, and significant reductions in both quality of life and self-esteem. Especially for men, this affectation is similar to that caused by erectile dysfunction., (Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.)

Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis., (© 2014 The Japanese Urological Association.)

Introduction: Advances in the treatment of interstitial cystitis or bladder pain syndrome (IC/BPS) depend on a good understanding of its pathogenesis. Presently, oral medicine and intravesical drug instillations may be the most popular therapies in daily practice. To improve the efficacy of intravesical drug delivery, the system requires modulation through coupling them to novel carriers. Numerous investigators have attempted alternative reconstructive procedures for bladder replacement/repair using scaffolds. These scaffolds include acellular extracellular matrix grafts or tissue-derived cell-seeded extracellular matrix grafts as well as the transplantation of mesenchymal progenitor cells into the damaged bladder., Areas Covered: This review focuses on the current available IC/BPS treatments and the different strategies employing nanotechnology or tissue engineering in the discovery of novel IC/BPS therapies., Expert Opinion: Current studies in the discovery of novel IC/BPS therapies are still imperfect, with novel approaches that use biocompatible nanomaterials or tissue engineering still ongoing. These nanoformulations give the benefit of protecting easily degradable molecules and enhance targeted delivery. Tissue engineering holds the promise of regenerating damaged tissues and organs by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues and organs. For these reasons, nanotechnology and tissue engineering could play key roles in the discovery of novel painful bladder syndrome therapies.

Background: The Overactive Bladder Syndrome (OAB) and the Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) are different urological conditions sharing 'urgency' as a common symptom. The aim of this review is to address our existing knowledge and establish how these symptoms are interrelated and to determine whether or not there is a common link between both symptoms complexes that help to distinguish one from the other., Methods: Pubmed was used to obtain references for this non-systematic review aiming to discuss differences between OAB and BPS/IC. Guidelines of several professional associations and discussions based on expert opinion from the authors were implemented., Results: Whilst in BPS the hallmark symptom is pain on bladder filling, urgency is the defining symptom of OAB. Whilst it is likely that the pain in BPS/IC arises from local inflammation in the bladder wall, the nature of urgency as a symptom, its origin, and the relationship between urgency and pain, as well as the different afferent mechanisms associated with the genesis of these sensory symptoms, remains unknown. Although the aetiology of both OAB and PBS/IC is unclear, the influence of environmental factors has been suggested. Both are chronic conditions with very variable symptom resolution and response to therapy. The relationship with voiding dysfunction, gynaecological causes of chronic pelvic pain or the possible alteration of the hypothalamic-pituitary-adrenal axis and psychological disorders has not been established. Inflammation has been suggested as the common link between OAB and BPS/IC., Conclusions: OAB and BPS/IC are different symptoms complexes that share urgency as a common symptom. None of them have a specific symptom although pain on bladder filling is the hallmark symptom in BPS/IC. Bladder pain with urgency should be a trigger for referral to the provider with appropriate knowledge and expertise in this disease state, whereas the management of OAB should be part of normal routine care in the community., (© 2013 John Wiley & Sons Ltd.)

Objective: To identify the risk factors in interstitial cystitis/painful bladder syndrome (IC/PBS) patients with lower urinary tract symptoms (LUTS) without urinary tract infection or benign prostate hyperplasia in China., Methods: A total of 954 outpatients with LUTS presenting for care to urology clinics at 8 hospitals throughout China from November 20, 2008 to August 24, 2012 were surveyed with a standardized questionnaire and validated outcome measures. The definitions for IC/PBS based on the O'Leary-Sant interstitial cystitis symptom and problem indices were used. The possible risk factors was analyzed with the Fisher's exact and Pearson chi-square tests. And multivariate predictive models were developed with binary Logistic regression methods., Results: There were 491 females and 463 males. And 44.7% (427/954) met the criteria for IC/PBS. There was significant gender difference (51.7% (254/491) vs 37.4% (173/463), P < 0.05) . After adjusting for confounding factors, bladder pain was significantly associated with stimulatory foods (OR: 81.16, 95%CI: 11.50-590.00, P = 0.001) and anorectal disease (OR: 54.90, 95%CI: 9.52-401.00, P = 0.001) in females. Caffeine beverage intake (OR: 4.29, 95%CI: 1.86-9.86, P = 0.001) was the only modifiable association according to multivariate analysis of males., Conclusions: Stimulatory foods, anorectal disease and caffeine beverages are potential risk factors for IC/PBS.Further studies are necessary to determine their roles in the pathogenesis of this disorder.

Interstitial cystitis/painful bladder syndrome (IC/PBS) remains a prevalent, but untreated disease with a poorly understood pathophysiology. Nonetheless, four main processes currently appear to be involved in producing IC/PBS symptoms: (1) disruption of the bladder GAG/proteoglycan layer, (2) upregulated immune/inflammatory response, (3) neural upregulation, and (4) pelvic floor dysfunction. Current and emerging therapies aimed at these potential targets will be the focus of this review with an update on IC/PBS therapy.