Interstitial Cystitis Research Articles

Antibiotics for UTI Prevention After Intradetrusor OnabotulinumtoxinA Injections.

Urinary tract infections (UTIs) occur in 8.6% to 48.1% of patients after intradetrusor onabotulinumtoxinA injections. The objective of this study was to evaluate both choice and duration of antibiotic prophylaxis on the incidence of UTI within 30 days after in-office onabotulinumtoxinA injections. We included a single-site, retrospective cohort of 305 patients with overactive bladder or bladder pain syndrome receiving postprocedure prophylactic antibiotics for in-office, 100-unit intradetrusor onabotulinumtoxinA injections from 2019 to 2023. Categories of antibiotic prophylaxis compared included (1) nitrofurantoin 100 mg twice daily for 3 days, (2) nitrofurantoin 100 mg twice daily for 5 days, (3) trimethoprim-sulfamethoxazole 160 mg/800 mg twice daily for 3 days, and (4) "other regimens." Primary outcome was incidence of UTI within 30 days. Variables were compared via χ2 test. Crude/adjusted odds were estimated using binary logistic regression. Incidence of UTI was 10.4% for 3-day nitrofurantoin, 20.5% for 5-day nitrofurantoin, 7.4% for 3-day trimethoprim-sulfamethoxazole, and 25.7% among "other regimens" (P = 0.023). Differences among primary regimens were substantial but not statistically significant: 3-day trimethoprim-sulfamethoxazole had 31% lower odds of UTI versus 3-day nitrofurantoin (odds ratio [OR], 0.689; P = 0.518). Compared with 3-day nitrofurantoin regimen, the 5-day nitrofurantoin regimen had twice the odds of UTI (OR, 2.22; P = 0.088). Those receiving "other regimens" had nearly 3 times the odds of UTI (OR, 2.98; P = 0.018). Results were similar adjusting for age and race. Overall urinary retention rate was 1.97%. Prophylactic antibiotic choice and duration of treatment potentially affect UTI incidence after in-office, intradetrusor onabotulinumtoxinA injections. Nitrofurantoin and trimethoprim-sulfamethoxazole for 3 days have the lowest UTI incidence.

Does treatment with daily antihistamines decrease the severity of interstitial cystitis symptoms?

Does treatment with daily antihistamines decrease the severity of interstitial cystitis symptoms?

Examination of Complementary Treatment Use of Individuals with Interstitial Cystitis: Descriptive Study

Objective: The aim of this study was to examine the use of complementary therapy in individuals with interstitial cystitis. Material and Methods: This study, which was carried out in a descriptive research design, was carried out with 80 female patients over 18 years of age with interstitial cystitis, who applied to the Urology Outpatient Clinic of a city hospital in Istanbul between January and July 2023. The data were collected by face-to-face (onsite) interview method using a form prepared by the researchers in line with the literature to determine the socio-demographic characteristics of the patients and their use of complementary therapy. Data were analyzed using SPSS 22 statistical software for Windows. Results are reported as mean ± SD. Ethics committee and institutional permission were obtained before starting the study. Results: When the characteristics of the individuals included in the study were examined; The mean age was 42.80±10.68 years, 60% did not have a chronic disease, 65% used any complementary treatment method, 43.2% used herbal treatment method, 50% did not receive complementary treatment. 55% received this information from the physician, 50% used complementary therapy to reduce their pain, 61.5% did not experience any side effects after using complementary therapy, 80.8% believed that complementary therapy was effective. It was determined that 53.8% of them did not share the complementary treatment methods they used with the physician or nurse. Conclusion: It was seen that the majority of individuals with interstitial cystitis used any complementary treatment, half of them did not get information before using the treatment, and more than half did not share the complementary treatment methods they used with the physician or nurse.

Urinary Viral Spectrum in Patients with Interstitial Cystitis/Bladder Pain Syndrome and the Clinical Efficacy of Valacyclovir Treatment.

Our previous study showed that the Epstein-Barr virus (EBV) may be the etiology for some patients with interstitial cystitis/bladder pain syndrome (IC/BPS); hence, the current study aimed to investigate the urinary viral spectrum in patients with IC/BPS and the clinical efficacy of valacyclovir. Twenty-eight patients were prospectively enrolled for valacyclovir 500 mg twice a day for 4 weeks. Urine samples were collected from IC/BPS patients and 30 controls. The primary outcome was the difference in the visual analog scale (VAS) pain score, and secondary outcomes included changes in the urinary viral spectrum and urinary inflammatory cytokine level (ClinicalTrials.gov Identifier: NCT05094414). Urinary EBV was detected in 14.2% IC/BPS patients but not in the controls. Urinary John Cunningham virus and BK virus were detected in 18 (64.3%) and 2 (7.1%) patients with IC/BPS, respectively, with similar prevalences noted for the controls. No cytomegalovirus, varicella-zoster virus, or herpes simplex virus was detected in the urine samples. The VAS pain score in patients with IC/BPS significantly decreased after 4 weeks (from 7.5 [5.52-9.0] to 5 [1.5-6.0], p = 0.0003). Urinary EBV was undetectable in any sample after valacyclovir treatment, and the decreases in urinary interleukin (IL)-1β (from 0.66 [0.55-0.82] pg/mL to 0.58 [0.55-0.64] pg/mL, p = 0.0034), IL-8 (from 6.81 [2.38 to 29.1] pg/mL to 4.33 [1.53-11.04] pg/mL, p = 0.0361), IL-10 (from 1.06 [0.94-1.18] pg/mL to 0.92 [0.88-1.02], p = 0.0086), and tumor necrosis factor-α (from 1.61 [1.50-1.72] pg/mL to 1.50 [1.44-1.55] pg/mL, p = 0.0079) were significant. Valacyclovir could relieve bladder pain, eliminate urinary EBV, and reduce bladder inflammation.

Pentosan Polysulfate Sodium Causes Diminished Function and Subtle Morphological Changes in Retina and RPE of Mice.

There are numerous reports of a distinctive maculopathy in adults exposed to pentosan polysulfate sodium (PPS), a drug prescribed to treat bladder discomfort associated with interstitial cystitis. We tested whether PPS treatment of mice injures RPE or retina to provide insight into the etiology of the human condition. Mice were fed PPS-supplemented chow over 14 months. RPE and retinal function was assessed by electroretinography (ERG) regularly. Following euthanasia, one eye was used for sagittal sectioning and histology, the contralateral for RPE flatmounting. ZO-1 positive RPE cell borders were imaged using confocal microscopy and cell morphology was analyzed using CellProfiler. After 10 months of PPS treatment, we observed diminution of mean scotopic c-wave amplitudes. By 11 months, we additionally observed diminutions of mean scotopic a- and b-wave amplitudes. Analysis of flatmounts revealed altered RPE cell morphology and morphometrics in PPS-treated mice, including increased mean en face cell area and geometric eccentricity, decreased RPE cell solidity and extent, and cytosolic translocation of alpha-catenin, all markers of RPE cell stress. Sex and regional differences were seen in RPE flatmount measures. Shortened photoreceptor outer segments were also observed. PPS treatment reduced RPE and later retina function as measured by ERG, consistent with a primary RPE injury. Post-mortem analysis revealed extensive RPE pleomorphism and polymegathism and modest photoreceptor changes. We conclude that PPS treatment of mice causes slowly progressing RPE and photoreceptor damage and thus may provide a useful model for some retinal pathologies.

Pelvic Floor Disorders Among Minority Women: Differences in Prevalence, Severity and Health-Related Social Needs

ObjectiveTo characterize prevalence and severity of pelvic floor disorders (PFDs) in various healthcare settings and to examine unmet Health-related Social Needs (HRSN) among minority women. Materials and MethodsMinority women with PFDs were recruited from our academic urogynecology clinic (UG), a general urology clinic at our institution’s safety net hospital (SNH), and a community outreach mobile clinic (MC). Questions from the Urinary Distress Index-6 (UDI), Pelvic Organ Prolapse Distress Inventory-6 (POPDI), and Female Genitourinary Pain Index (GUPI) were used to identify patients with stress urinary incontinence (SUI), overactive bladder (OAB) and chronic pelvic pain syndrome (CPPS). Results61 (46.6%) women identified as Hispanic, 53 (40.4%) as Black, and 17 (12.9%) as Other. Overall, self-reported PFDs included SUI in 45%, OAB in 74.8%, and CPPS in 24.4% of women. Hispanic women were more likely to report OAB symptoms, compared to Black women (OR 3.4 [1.2-10.2], p = 0.03) or Other women (OR = 5.1 [1.3-20.4], p = 0.02). Participants held a median of five unmet HRSN. Minority women facing issues with family and community support, transportation, and utilities were more likely to report CPPS symptoms, compared to those without psychosocial issues (Support OR: 4.8 [1.7-13.7], p = 0.002; Transportation OR: 2.0 [1.0-8.2], p = 0.05; Utility OR: 7.0 [1.9-28.1], p = 0.005). ConclusionMinority women with PFDs may have several unmet HRSNs which impact their ability to receive appropriate medical care. Our findings may assist in the development of effective strategies to improve healthcare outcomes for women dealing with PFDs.

Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.

To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS). Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot. The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05). These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.

Bioenergetic profiles of peripheral mononuclear cells and systemic inflammation in women with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS).

Inflammation is thought to contribute to the etiology of interstitial cystitis/bladder pain syndrome (IC/BPS). It is well-known that disruption in metabolism in immune cells contributes to inflammation in several inflammatory diseases. The purpose of this study was to investigate whether cellular bioenergetics is altered in monocytes and lymphocytes from women with IC/BPS, and if these alterations correlate with systemic inflammatory markers. Age and BMI matched adult healthy women (HS; n = 18) and women with IC/BPS (n = 18) were included in the study. Blood was collected to assess cellular bioenergetics in monocytes and lymphocytes using a Seahorse XF96 Analyzer and plasma cytokine levels were measured using Meso Scale Discovery immunoassays. The correlation between bioenergetic parameters, cytokines, and demographics was determined using Pearson correlation coefficients. Means of the two groups were compared using the two-group t-test. Patients with IC/BPS had reduced monocyte oxygen consumption rates and glycolytic rates compared to healthy subjects. In contrast, lymphocytes from these patients had increased oxygen consumption rates and glycolytic rates. Several cytokines and chemokines including Interferon-gamma (IFN-ɣ), tumor necrosis factor alpha (TNF-ɑ), Interleukin-6 (IL-6), Interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) levels were significantly elevated in the plasma of patients with IC/BPS. However, Transforming growth factor (TGF-β) and Interleukin-10 (IL-10) levels were significantly decreased in IC/BPS patients compared to HS. In addition, Interferon gamma (IFN-ɣ), TNF-ɑ, IL-8, and TGF-β levels correlated with several bioenergetic parameters in monocytes or lymphocytes from healthy subjects. In contrast, TNF-ɑ and IL-8 correlated with bioenergetic parameters in monocytes from IC/BPS patients. Monocyte and lymphocyte cellular bioenergetics and plasma cytokine levels are different in patients with IC/PBS compared to HS. It appears that systemic inflammation is greater in this cohort which may negatively impact immune cell function. The relationship between cellular bioenergetics and inflammation in monocytes and lymphocytes could be important in understanding the pathogenesis of IC/PBS and warrants further investigation.

Understanding the sleep-pain relationship in patients with interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain condition with critical symptoms of urinary urgency and frequency, persistent bladder-related pain, and reduced quality of life. Poor-quality sleep can lead to significant disturbances in daily life and increased pain in IC/BPS patients. Resilience, depressive symptoms, and pain catastrophizing have univariate associations with sleep and pain in IC/BPS, suggesting they may be mechanisms in this sleep and pain relationship. This online study recruited patients self-reporting a diagnosis of IC/BPS through support groups, social media posts (Facebook, Reddit, and Instagram), and urology clinic advertisements. Participants completed questionnaires on demographics, urologic symptoms, pain, pain catastrophizing, depressive symptoms, and resilience. Only those participants who met the RAND Interstitial Cystitis Epidemiology (RICE) criteria for IC/BPS diagnosis were included. A multiple mediation model was first examined, followed by a serial mediation model. Seventy-four participants (Mage= 47.0, standard deviation [SD ] 16.7, range 18-83 years) met inclusion criteria. A multiple mediation model showed greater sleep disturbance was associated with greater pain severity through depressive symptoms and pain catastrophizing, but not resilience (b=0.79, bootSE =0.26, bootCI [0.33, 1.35]). A serial mediation showed that the sleep-to-pain relationship had a significant indirect effect through pain catastrophizing and depressive symptoms (b=0.78, bootSE =0.26, bootCI [0.35, 1.32]). Findings suggest depressive symptoms and pain catastrophizing may be important psychosocial mechanisms in the sleep-to-pain relationship. These results help guide future sleep and pain research in IC/BPS and aid in developing and refining treatments.

The Model of Interstitial Cystitis for Evaluating New Molecular Strategies of Interstitial Regeneration in Humans.

Given the recent evidence in the clinical application of regenerative medicine, mostly on integumentary systems, we focused our interests on recent bladder regeneration approaches based on mesenchymal stem cells (MSCs), platelet-rich plasma (PRP), and hyaluronic acid (HA) in the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. IC/BPS is a heterogeneous chronic disease with not-well-understood etiology, characterized by suprapubic pain related to bladder filling and urothelium dysfunction, in which the impairment of immunological processes seems to play an important role. The histopathological features of IC include ulceration of the mucosa, edema, denuded urothelium, and increased detection of mast cells and other inflammatory cells. A deeper understanding of the molecular mechanism underlying this disease is essential for the selection of the right therapeutic approach. In fact, although various therapeutic strategies exist, no efficient therapy for IC/BPS has been discovered yet. This review gives an overview of the clinical and pathological features of IC/BPS, with a particular focus on the molecular pathways involved and a special interest in the ongoing few investigational therapies in IC/BPS, which use new regenerative medicine approaches, and their synergetic combination. Good knowledge of the molecular aspects related to stem cell-, PRP-, and biomaterial-based treatments, as well as the understanding of the molecular mechanism of this pathology, will allow for the selection of the right and best use of regenerative approaches of structures involving connective tissue and epithelia, as well as in other diseases.

Interstitial cystitis – a diagnostic dilemma: A case report

Background: Interstitial cystitis is a debilitating condition with a rising prevalence due to increasedresearch and diagnostic criteria. Interstitial cystitis falls under the category of urologic chronic pelvic painsyndrome and is a diagnosis of exclusion. Interstitial cystitis or bladder pain syndrome (BPS) ischaracterized by chronic inflammation. Common symptoms include chronic pelvic pain, pressure, ordiscomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, suchas persistent urge to void or urinary frequency in the absence of confusable diseases (hypersensitivebladder symptoms). The true burden of interstitial cystitis is underestimated, and the economic burden ofthe disease is due to multiple office visits and an increase in direct medical costs.Case presentation: A 59-year-old para 2+0 (2 previous scars) postmenopausal with a 1-year history offrequency (up to eight episodes) nocturia with low abdominal pain. Her urinalysis profile, urea,electrolytes and creatinine, and ultrasound and computed tomography of the kidneys, ureters andbladder, pap smear, and random blood sugar tests were unremarkable. Cystoscopy was hemorrhagicwith biopsy histology showing ulcerated bladder mucosa with numerous plasma cells, eosinophils, andneutrophils in the lamina propria no atypia, with fibrosis and dilated capillaries in the lamina propria. Onfollow-up she had a recurrence of pain symptoms with a cystoscopy biopsy, seven months later showingplasma cell infiltrate with ulceration of the overlying urothelium, and congestion of the blood vessels. Shewas not neoplastic and was put on antihistamine, nonsteroidal antiinflammatory drugs, and solifen.Conclusion: Prompt diagnosis and treatment of interstitial cystitis will reduce the burden of diseaseassociated with multiple outpatient visits and unnecessary use of antibiotics. The mainstay ofmanagement is oral and intravesical treatment with surgery in refractory cases.

The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1β (IL-1β), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 μM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 μM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1β (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 μM), and 500 μM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C-fos immunohistochemistry study.

Although the co-occurrence of interstitial cystitis (IC) and endometriosis (ENDO) is remarkably high, the exact pathophysiology for this co-occurrence is unknown. The convergence of the inputs from the involved structures to the same neuronal centers may suggest neuronal hyperexcitability as a mechanism for this co-occurrence. The present study aimed to investigate the association between IC and ENDO, by studying the changes in brainstem responses to cystometry in a rat model of ENDO and cyclophosphamide (CYP)-induced IC using c-fos immunohistochemistry. Following cystometry the brainstem areas that had significant increase in c-fos expression in ENDO alone included: periaqueductal gray (PAG) nuclei, dorsal raphe nucleus, raphe obscurus nucleus, kolliker- Fuse areas, and area postrema. However, the brainstem areas that had increased significantly in the c-fos expression in the ENDO and CYP treated animals included: gigantocellular nucleus, lateral paragigantocellular nucleus, caudoventrolateral nucleus, rostroventrolateral/caudoventrolateral nucleus, lateral reticular nucleus, locus coeruleus, lateral PAG, raphe pallidus nucleus, raphe magnus nucleus, rostroventrolateral nucleus, dorsal motor nucleus of vagus, and solitary tract nucleus. Whereas only lateral parabrachial nucleus showed significant increase in c-fos expression in CYP treated animals alone. The results of the present study demonstrate the overlap of brainstem nuclei that are excited by urinary bladder under ENDO and IC conditions. The pattern of hyperexcitability of the brainstem nuclei may help in understating the pathophysiology of IC and ENDO conditions.

Quality of Life and Treatment Modalities in Patients with Interstitial Cystitis: The Patients' Perspective.

Quality of life (QoL)-based outcomes are hardly incorporated into interstitial cystitis/bladder pain syndrome (IC/BPS) guidelines, because studies are limited and outdated. Therefore, guidelines might not reflect the current clinical situation accurately. Secondly, guidelines suggest using a multimodal approach for BPS/IC management, but data on the patient-perceived efficacy of these therapies are limited. The aim of this study is to investigate the perception of IC/BPS patients of their QoL, to determine which treatments they have received, and to examine how they evaluate the efficacy of these various (alternative) therapies. A quantitative retrospective database evaluation was performed, with data from an existing IC/BPS patient survey (n = 217) that was conducted in 2021. This survey contained QoL data based on validated questionnaires such as EQ-5D 5L. The QoL of patients is affected significantly by IC/BPS. This is evident from the various affected domains on the EQ-5D 5L. The symptom severity was negatively affected by a delay in diagnosis, and there were clear differences in QoL domains between females and males. Secondly, coagulation therapy and intravesical glycosaminoglycan (GAG) therapy were most appreciated by patients. Other (alternative) treatments were commonly utilized, although some had doubtful results and high discontinuation rates. QoL is considerably impaired in IC/BPS patients. The diverse responses and adherence to various treatments warrant a personalized approach (phenotype-oriented therapy). To achieve QoL improvement, it is important to incorporate the patient's perspective in treatment guidelines.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Mechanisms of oxidative stress in interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by bladder and/or pelvic pain, increased urinary urgency and frequency and nocturia. The pathophysiology of IC/BPS is poorly understood, and theories include chronic inflammation, autoimmune dysregulation, bacterial cystitis, urothelial dysfunction, deficiency of the glycosaminoglycan (GAG) barrier and urine cytotoxicity. Multiple treatment options exist, including behavioural interventions, oral medications, intravesical instillations and procedures such as hydrodistension; however, many clinical trials fail, and patients experience an unsatisfactory treatment response, likely owing to IC/BPS phenotype heterogeneity and the use of non-targeted interventions. Oxidative stress is implicated in the pathogenesis of IC/BPS as reactive oxygen species impair bladder function via their involvement in multiple molecular mechanisms. Kinase signalling pathways, nociceptive receptors, mast-cell activation, urothelial dysregulation and circadian rhythm disturbance have all been linked to reactive oxygen species and IC/BPS. However, further research is necessary to fully uncover the role of oxidative stress in the pathways driving IC/BPS pathogenesis. The development of new models in which these pathways can be manipulated will aid this research and enable further investigation of promising therapeutic targets.

Hispidulin targets PTGS2 to improve cyclophosphamide-induced cystitis by suppressing NLRP3 inflammasome.

Interstitial cystitis (IC) is a chronic bladder inflammation. Inhibition of prostaglandin G/H synthase 2 (PTGS2) is the most common method for controlling inflammation-related diseases. This study aimed to analyze the effects of hispidulin on the PTGS2 and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammation in experimental IC models. A binding activity between hispidulin and PTGS2 was measured using molecular docking. Human urothelial cells (SV-HUC-1) were stimulated by 2ng/mL of interleukin (IL)-1β for 24h and cultured in a medium with different concentrations of hispidulin (2.5, 5, 10, 20µM) for 24h to observe the expressions of PTGS2 and NLRP3 protein. Cells overexpressing PTGS2 were established by PTGS2 cDNA transfection. In the IL-1β-treated cells, the NLRP3 inflammasome was measured after 20µM hispidulin treatment. In rats, animals were performed with three injections of 40mg/kg cyclophosphamide (CYP) and orally treated with 50mg/kg/day hispidulin or ibuprofen for 3days. The bladder pain was measured using Von Frey filaments, and the bladder pathology was observed using hematoxylin and eosin (H&E) staining. The expressions of PTGS2 and NLRP3 inflammasome were also observed in the bladder tissues. A good binding activity was found between hispidulin and PTGS2 (score = - 8.9kcal/mol). The levels of PTGS2 and NLRP3 inflammasome were decreased with the hispidulin dose increase in the IL-1β-treated cells (p < 0.05). Cells overexpressing PTGS2 weakened the protective effects of hispidulin in the IL-1β-treated cells (p < 0.01). In the CYP-treated rats, hispidulin treatment improved the bladder pain through decreasing the nociceptive score (p < 0.01) and suppressed the bladder inflammation through suppressing the expressions of PTGS2 and NLRP3 inflammasome in bladder tissues (p < 0.01). Additionally, the results of ibuprofen treatment were similar to the effects of hispidulin in the CYP-treated rats. This study demonstrates that hispidulin may be a new alternative drug for the IC treatment that binds PTGS2 to perform its functions.

(267) The Prevalence of Conditions Involving Aberrant Mast Cell Activity in Patients with Neuroproliferative Vestibulodynia

Abstract Introduction Neuroproliferative vestibulodynia (NPV) is a provoked vestibular pain, shown to be associated with excess immunohistochemical staining for CD117 and PGP9.5, consistent with mast cells and nerves, respectively. It is hypothesized that NPV occurs in genetically predisposed patients in whom mast cells accumulate in the vestibular sub-epithelial stroma where they release various cytokines/growth factors that stimulate the growth of nerves, causing severe allodynia and hyperalgesia throughout the entire vestibule. Objective To assess, in our patient cohort with histopathologically confirmed diagnosis of NPV, the prevalence of concomitant conditions involving aberrant mast cell activity. Methods Medical records from people with vulvas who underwent vestibulectomy between June 1, 2019 and December 31, 2022 were retrospectively reviewed. This research protocol was IRB-exempt. Histories from these patients, all of whom had histopathologically confirmed NPV after observing &amp;gt; 8 immunopositive CD117 stained cells per high-power field in the sub-epithelial stroma, were reviewed. The prevalence was noted for the presence of concomitant conditions where aberrant mast cell activity has been reported to play a critical role in symptomatology. The focus was on the following eight conditions: asthma, chronic sinusitis, endometriosis, food allergy/intolerance, interstitial cystitis, irritable bowel syndrome, migraine, and postural orthostatic tachycardia syndrome. Results A total of 65 NPV patients were included in this chart review. While 24 (37%) reported none, 41 (63%) had at least one other concomitant condition involving aberrant mast cell activity. A total of 25 (38%), 10 (15%), 4 (6%) and 2 (3%) had one, two, three and five other conditions, respectively, involving aberrant mast cell activity. The most common such condition was migraine (n=14; 22%), followed by endometriosis (n=12; 19%), food allergy/intolerance (n=11; 17%), interstitial cystitis (n=10; 15%), irritable bowel syndrome (n=8; 12%), asthma (n=7; 11%), chronic sinusitis (n=5; 8%) and postural orthostatic tachycardia syndrome (n=2; 3%). There was no correlation between the number of concomitant conditions with aberrant mast cell activity reported and the density of CD117-immunopositive staining in the overall cohort of patients with NPV or within the subgroups of those with either lifelong or acquired NPV. Conclusions Patients with histopathologically confirmed NPV have a high prevalence of concomitant conditions associated with aberrant mast cell activity. While more studies are needed, NPV is likely part of a broader systemic collection of conditions associated with aberrant mast cell activity. This finding is relevant in terms of future diagnostic and treatment options for patients with NPV. Disclosure No.

(266) Miconazole Vaginal Cream-Induced Acquired Neuroproliferative Vestibulodynia

Abstract Introduction The endodermal vestibule lies between the ectodermal vulva and the mesodermal vagina. Unlike the vulvar skin, the vestibular epithelium is thin, non-keratinized, and its submucosal immune cells are more susceptible to activation. Topical pharmaceutical agents that are applied to the genitals for various medical indications are likely to contact the vestibular epithelium. For example, miconazole vaginal cream (MVC) is approved for treatment of vaginal yeast infections and the irritation associated with the yeast infection. Active and inactive ingredients in MVC include miconazole nitrate, benzoic acid, cetyl alcohol, isopropyl myristate, polysorbate 60, potassium hydroxide, propylene glycol, purified water and stearyl alcohol. We have observed cases where individuals, previously without vestibular pain, have applied MVC to their genitals and immediately experienced excruciating burning that resulted in persistent unrelenting severe pain throughout the vestibule, which is a symptom of acquired neuroproliferative vestibulodynia (ANPV). Objective Our objective is to report cases of patients who used MVC and were diagnosed with ANPV in order to provide awareness of this condition. Methods We performed a retrospective chart review of persons with vulvas presenting to a single sexual medicine clinic between 6/2019-6/2023 who were clinically suspected to have ANPV after experiencing an allergic reaction following use of MVC. Patients were included who failed conservative treatments for provoked vestibular pain, underwent vestibulectomy and were histopathlogically diagnosed with ANPV (&amp;gt;8 CD117 stained immunopositive cells per high-power field (HPF), consistent with mast cells, and excess PGP117 stained immunopositive cells, consistent with nerves). Demographic data, prior diagnoses and treatments, and results from validated questionnaires were collected. Results Our patient cohort included 7 individuals who met the criteria for MVC-induced ANPV. Mean age at time of MVC-induced vestibular pain was 23 (range 18-29) years. Mean age of presentation to our sexual medicine facility was 28 (range 22-33) years. Mean years of delay in diagnosis of MVC-induced ANPV was 5 (range 1-12) years. 71% and 29% were previously diagnosed and unsuccessfully managed as hormone-mediated vestibulodynia and interstitial cystitis, respectively. The mean pain score and overall score for the Female Sexual Function Index (FSFI) was 1.2/6 (range 0-3.2/6) and 11.7/36 (range 4.2-18.1/36), respectively. All total FSFI scores were &amp;lt;26 and indicative of sexual dysfunction. The mean Female Sexual Distress Scale-Revised score was 32.2/52 (21-39/52), consistent with significant distress. Conclusions Our cohort of patients with MVC-induced ANPV experienced several years of misdiagnoses, unsuccessful treatments, and significant pain and distress. It is hypothesized that MVC induces ANPV in genetically susceptible individuals possibly due to activation of the innate submucosal immune cells from an allergic reaction to active or inactive ingredients in the MVC. This allergic reaction results in accumulation of mast cells in the subepithelial stroma that release cytokines and growth factors leading to proliferation of nerves with subsequent symptoms of allodynia and hyperalgesia. Avoidance of topical medications and use of systemic antifungal strategies in individuals with yeast infections may be advisable. Disclosure No.

MiR-9-enriched mesenchymal stem cells derived exosomes prevent cystitis-induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice.

Inflammatory response of central nervous system is an important component mechanism in the bladder pain of interstitial cystitis/bladder pain syndrome (IC/BPS). Exosomes transfer with microRNAs (miRNA) from mesenchymal stem cell (MSCs) might inhibit inflammatory injury of the central nervous system. Herein, the purpose of our study was to explore the therapeutic effects by which extracellular vesicles （EVs） derived from miR-9-edreched MSCs in IC/BPS and further investigate the potential mechanism to attenuate neuroinflammation. On the basis of IC/BPS model, we used various techniques including bioinformatics, cell and molecular biology, and experimental zoology, to elucidate the role and molecular mechanism of TLR4 in regulating the activation of NLRP3 inflammasome in bladder pain of IC/BPS, and investigate the mechanism and feasibility of MSC-EVs enriched with miR-9 in the treatment of bladder pain of IC/BPS. The inflammatory responses in systemic and central derived by TLR4 activation were closely related to the cystitis-induced pelvic/bladder nociception in IC/BPS model. Intrathecal injection of miR-9-enreched MSCs derived exosomes were effective in the treatment of cystitis-induced pelvic/bladder nociception by inhibiting TLR4/NF-κb/NLRP3 signal pathway in central nervous system of IC/BPS mice. This study demonstrated that miR-9-enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis-induced bladder pain by inhibiting TLR4/NF-κb/NLRP3 signal pathway in interstitial cystitis mice, which is a promising strategy against cystitis-induced bladder pain.