Examination of pelvic floor muscle elasticity in patients with interstitial cystitis/bladder pain syndrome using real-time tissue elastography.

INTRODUCTION AND HYPOTHESIS: The aim was to compare pelvic floor muscle (PFM) elasticity between interstitial cystitis/bladder pain syndrome (IC/BPS) patients and healthy women using real-time tissue elastography. METHODS: The subjects were 17 IC/BPS female patients (IC/BPS group; age 34-84 years), 10 healthy middle-aged women (middle-aged group; 50-80 years), and 17 healthy young adult women (young group; 23-37 years). The target sites of elastography were the striated urethral sphincter (SUS) and adipose tissue as the reference site; muscle elasticity was calculated as the strain ratio (SR) of the SUS to the reference site. Evaluations were performed at rest and during PFM contraction. The IC/BPS group completed lower urinary tract symptom and pain questionnaires. SUS SR was compared among the three groups. SUS SR at rest and during PFM contraction was compared among the three groups with the t-test and the Wilcoxon test. Associations between questionnaire results and SUS SR were evaluated by correlation analysis. RESULTS: There was no significant difference in age between the IC/BPS and middle-aged groups, but the young group was significantly younger than the other groups (p < 0.001). SUS SR at rest was significantly higher in the IC/BPS group than in the middle-aged (p = 0.014) and young groups (p = 0.002). Furthermore, in the IC/BPS group, there was no significant difference in SUS SR between at rest and during PFM contraction. SUS SR was not significantly correlated with questionnaire results for lower urinary tract symptoms. CONCLUSIONS: SUS SR at rest was significantly higher in the IC/BPS group than in the young and middle-aged groups.

A H2O2-activatable nanoprobe for diagnosing interstitial cystitis and liver ischemia-reperfusion injury via multispectral optoacoustic tomography and NIR-II fluorescent imaging.

Developing high-quality NIR-II fluorophores (emission in 1000-1700 nm) for in vivo imaging is of great significance. Benzothiadiazole-core fluorophores are an important class of NIR-II dyes, yet ongoing limitations such as aggregation-caused quenching in aqueous milieu and non-activatable response are still major obstacles for their biological applications. Here, we devise an activatable nanoprobe to address these limitations. A molecular probe named BTPE-NO2 is synthesized by linking a benzothiadiazole core with two tetraphenylene groups serving as hydrophobic molecular rotors, followed by incorporating two nitrophenyloxoacetamide units at both ends of the core as recognition moieties and fluorescence quenchers. An FDA-approved amphiphilic polymer Pluronic F127 is then employed to encapsulate the molecular BTPE-NO2 to render the nanoprobe BTPE-NO2@F127. The pathological levels of H2O2 in the disease sites cleave the nitrophenyloxoacetamide groups and activate the probe, thereby generating strong fluorescent emission (950~1200 nm) and ultrasound signal for multi-mode imaging of inflammatory diseases. The nanoprobe can therefore function as a robust tool for detecting and imaging the disease sites with NIR-II fluorescent and multispectral optoacoustic tomography (MSOT) imaging. Moreover, the three-dimensional MSOT images can be obtained for visualizing and locating the disease foci.

Functional and histologic imaging of urinary bladder wall after exposure to psychological stress and protamine sulfate.

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Abnormal functional connectivity within the prefrontal cortex in interstitial cystitis/bladder pain syndrome (IC/BPS): A pilot study using resting state functional near-infrared spectroscopy (rs-fNIRS).

PURPOSE: To investigate the abnormalities of functional connectivity (FC) within the prefrontal cortex (PFC) of patients with interstitial cystitis/bladder pain syndrome (IC/BPS) based on resting state functional near-infrared spectroscopy (rs-fNIRS) data using FC matrix analysis. MATERIALS AND METHODS: Ten patients with IC/BPS (females, 9; mean age, 56.9 ± 12.432 years) and 15 age- and gender-matched healthy controls (HC) (females, 12; mean age, 55.067 ± 7.46 years) participated in this rs-fNIRS study. Two rs-fNIRS scans were performed (when the bladder was empty and when the desire to void was strong). The Pearson's correlation coefficient between the time series of the 22 channels was calculated to obtain a 22 × 22 FC matrix for each subject. A two-sample t-test (p < .05) was performed to compare group differences in the FC matrix between patients with IC/BPS and HC. RESULTS: FC was significantly decreased within the PFC in the IC/BPS group based on a two-sample t-test (p < .05) compared with HC. FC decreased in a wider range of brain regions during the strong desire to void state (4 brain regions and 28 edges) when compared with the empty bladder state (3 brain regions and 18 edges). CONCLUSION: FC abnormalities in IC/BPS patients may lead to frontal lobe disorders involved in processing sensory integration, motivation drive, emotional control, and decision-making whether to urinate, leading to urinary control dysfunction manifested as typical clinical IC/BPS symptoms. Our results may provide new insight into the pathogenesis of IC/BPS and new brain biomarkers for diagnosis.

SuperGAG biopolymers for treatment of excessive bladder permeability.

Few therapeutic options exist for treatment of IC/BPS. A novel high MW GAG biopolymer ("SuperGAG") was synthesized by controlled oligomerization of CS, purified by TFF and characterized by SEC-MALLS and 1H-NMR spectroscopy. The modified GAG biopolymer was tested in an OVX female rat model in which bladder permeability was induced by a 10-minute intravesicular treatment with dilute (1 mg/ml) protamine sulfate and measured by classical Ussing Chamber TEER measurements following treatment with SuperGAG, chondroitin sulfate, or saline. The effect on abrogating the abdominal pain response was assessed using von Frey filaments. The SuperGAG biopolymer was then investigated in a second, genetically modified mouse model (URO-MCP1) that increasingly is accepted as a model for IC/BPS. Permeability was induced with a brief exposure to a sub-noxious dose of LPS and was quantified using contrast-enhanced MRI (CE-MRI). The SuperGAG biopolymer restored impermeability to normal levels in the OVX rat model as measured by TEER in the Ussing chamber and reduced the abdominal pain response arising from induced permeability. Evaluation in the URO-MCP1 mouse model also showed restoration of bladder impermeability and showed the utility of CE-MRI imaging for evaluating the efficacy of agents to restore bladder impermeability. We conclude novel high MW SuperGAG biopolymers are effective in restoring urothelial impermeability and reducing pain produced by loss of the GAG layer on the urothelium. SuperGAG biopolymers could offer a novel and effective new therapy for IC/BPS, particularly if combined with MRI to assess the efficacy of the therapy.

Role of Diffusion-Weighted Magnetic Resonance Imaging in the Diagnosis of Bladder Pain Syndrome/Interstitial Cystitis.

Some recent studies evaluated the introduction of diffusion-weighted magnetic resonance imaging (DW-MRI) in the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC). OBJECTIVE: To evaluate whether DW-MRI can contribute to noninvasive diagnosis of BPS/IC. The agreement between two raters (2 radiologists involved in the study) was also evaluated, the relevance of the "operator-dependent" factor defined. PATIENTS AND METHODS: Twenty-two female patients with a diagnosis of BPS-IC were recruited and performed DW-MRI. The same investigation was also performed in 20 patients with pelvic gynecological diseases and no BPS-IC. RESULTS: A significant difference was found between BPS-IC and no-BPS-IC since 17 out of 22 subjects of the first group were positive, compared to 3 out of 20 no-IC subjects, with a P value of .001 to highlight the statistical significance. The sensitivity of the exam was 77%, while the specificity was 85%. There was good agreement between the 2 raters in the evaluation of MRI results. CONCLUSION: DW-MRI helps to obtain a noninvasive diagnosis of BPS/IC, by providing useful information on the choice of which patients may be more appropriately submitted to cystoscopy and bladder biopsy.

Lupus cystitis: unusual cause of renal failure in systemic lupus erythematosus.

A 42-year-old woman presented with chronic fever, abdominal pain, intermittent loose stools and dysuria for 3 months. She had recently developed acute dyspnoea with acute kidney injury. She was found to have a contracted, thick-walled bladder with bilateral hydroureteronephrosis. She underwent bilateral percutaneous nephrostomies, following which her renal function recovered. She satisfied the clinical and immunological features of the Systemic Lupus International Collaborating Clinics criteria for systemic lupus erythematosus (SLE). She was initiated on immunosuppression. Lupus cystitis with a contracted bladder is an uncommon presentation of SLE.

Is bladder blood flow an etiologic factor for the bladder pain syndrome?

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.

Diffusion-Weighted Magnetic Resonance Imaging: A New Tool for the Diagnosis of Bladder Pain Syndrome/Interstitial Cystitis.

OBJECTIVES: To determine whether diffusion-weighted magnetic resonance imaging (DWMRI), a noninvasive procedure, can contribute to the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: The pelvic DWMRI of patients with chronic pelvic pain syndrome was selected between January 2012 and June 2017. A radiologist analyzed the bladder wall signal; he was blinded to the patients' clinical data. According to the 2008 European Society for the Study of Bladder Pain Syndrome/Interstitial Cystitis criteria, 2 groups of patients were determined: BPS/IC and no BPS/IC. The association between BPS/IC and the wall signal intensity was compared. RESULTS: In the 106 patients included, 82 had criteria for BPS/IC and 24 did not. A significant difference in the distribution of the signal was found between the 2 groups (p = 0.01). High signal intensity of the bladder wall was related to the presence of a BPS/IC with a sensitivity of 28% and a specificity of 88%. No signal intensity of the bladder wall was related to the absence of a BPS/IC with a sensitivity of 96% and a specificity of 29%. CONCLUSIONS: In -DWMRI, high bladder wall signal intensity helps to affirm a BPS/IC, whereas the absence of signal helps to exclude the diagnosis. Further studies are needed to confirm these preliminary results.

Longitudinal intravital imaging of transplanted mesenchymal stem cells elucidates their functional integration and therapeutic potency in an animal model of interstitial cystitis/bladder pain syndrome.

Rationale: Mesenchymal stem cell (MSC) therapy may be a novel approach to improve interstitial cystitis/bladder pain syndrome (IC/BPS), an intractable disease characterized by severe pelvic pain and urinary frequency. Unfortunately, the properties of transplanted stem cells have not been directly analyzed in vivo, which hampers elucidation of the therapeutic mechanisms of these cells and optimization of transplantation protocols. Here, we monitored the behaviors of multipotent stem cells (M-MSCs) derived from human embryonic stem cells (hESCs) in real time using a novel combination of in vivo confocal endoscopic and microscopic imaging and demonstrated their improved therapeutic potency in a chronic IC/BPS animal model. Methods: Ten-week-old female Sprague-Dawley rats were instilled with 10 mg of protamine sulfate followed by 750 µg of lipopolysaccharide weekly for 5 weeks. The sham group was instilled with phosphate-buffered saline (PBS). Thereafter, the indicated dose (0.1, 0.25, 0.5, and 1×106 cells) of M-MSCs or PBS was injected once into the outer layer of the bladder. The distribution, perivascular integration, and therapeutic effects of M-MSCs were monitored by in vivo endoscopic and confocal microscopic imaging, awake cystometry, and histological and gene expression analyses. Results: A novel combination of longitudinal intravital confocal fluorescence imaging and microcystoscopy in living animals, together with immunofluorescence analysis of bladder tissues, demonstrated that transplanted M-MSCs engrafted following differentiation into multiple cell types and gradually integrated into a perivascular-like structure until 30 days after transplantation. The beneficial effects of transplanted M-MSCs on bladder voiding function and the pathological characteristics of the bladder were efficient and long-lasting due to the stable engraftment of these cells. Conclusion: This longitudinal bioimaging study of transplanted hESC-derived M-MSCs in living animals reveals their long-term functional integration, which underlies the improved therapeutic effects of these cells on IC/BPS.

Recent advances in imaging and understanding interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition associated with intense pelvic pain and bladder storage symptoms. Since diagnosis is difficult, prevalence estimates vary with the methodology used. There is also a lack of proven imaging tools and biomarkers to assist in differentiation of IC/BPS from other urinary disorders (overactive bladder, vulvodynia, endometriosis, and prostatitis). Current uncertainty regarding the etiology and pathology of IC/BPS ultimately impacts its timely and successful treatment, as well as hampers future drug development. This review will cover recent developments in imaging methods, such as magnetic resonance imaging, that advance the understanding of IC/BPS and guide drug development.

Novel contrast mixture achieves contrast resolution of human bladder wall suitable for T1 mapping: applications in interstitial cystitis and beyond.

PURPOSE: Instillation of novel contrast mixture (NCM) was recently shown to improve the contrast resolution of rat bladder wall with high contrast-to-noise ratio (CNR). Here, the clinical safety and the feasibility of NCM-enhanced MRI to achieve artifact-free visualization of human bladder wall suitable for quantitative measurement of the magnetic resonance (MR) longitudinal relaxation time (T1) was assessed. METHODS: Six female subjects [two controls and two with Hunner-type interstitial cystitis IC and two with non-Hunner-type IC] consented for MRI at 3 T before and after instillation of NCM [4 mM gadobutrol and 5 mM ferumoxytol in 50 mL of sterile water for injection]. Single breath-hold fast MR acquisition in large readout bandwidth for 5-mm-thick single slice with variable flip angle was applied to minimize the motion and chemical shift artifacts in measurements of bladder wall thickness (BWT), CNR and T1 from 20 pixels. RESULTS: NCM instillation in subjects did not evoke pain or discomfort. Fourfold increase in bladder wall CNR (*p < 0.02) and pixel size of 0.35 mm with minimal influence of artifacts allowed accurate determination of bladder wall thinning ~ 0.46 mm from 50 mL NCM (*p < 0.05). Pre-contrast bladder wall T1 of 1544 ± 34.2 ms was shortened to 860.09 ± 13.95 ms in Hunner-type IC (*p < 0.0001) relative to only 1257.42 ± 20.59 and 1258.16 ± 6.16 ms in non-Hunner-type IC and controls, respectively. CONCLUSION: Findings demonstrate the safety and feasibility of NCM-enhanced MRI to achieve artifact-free differential contrast and spatial resolution of human bladder wall, which is suitable for measuring BWT and pixel-wise measurement of T1 in post-contrast setting.

A noninvasive bladder sensory test supports a role for dysmenorrhea increasing bladder noxious mechanosensitivity.

OBJECTIVE: Catheterization to measure bladder sensitivity is aversive and hinders human participation in visceral sensory research. Therefore, we sought to characterize the reliability of sonographically estimated female bladder sensory thresholds. To demonstrate this technique's usefulness, we examined the effects of self-reported dysmenorrhea on bladder pain thresholds. METHODS: Bladder sensory threshold volumes were determined during provoked natural diuresis in 49 healthy women (mean age, 24±8 y) using 3-dimensional ultrasound. Cystometric thresholds (Vfs, first sensation; Vfu, first urge; Vmt, maximum tolerance) were quantified and related to bladder urgency and pain. We estimated the reliability (1-wk retest and interrater). Self-reported menstrual pain was examined in relationship to bladder pain, urgency, and volume thresholds. RESULTS: Average bladder sensory thresholds (mL) were Vfs (160±100), Vfu (310±130), and Vmt (500±180). Interrater reliability ranged from 0.97 to 0.99. One-week retest reliability was Vmt=0.76 (95% CI, 0.64-0.88), Vfs=0.62 (95% CI, 0.44-0.80), and Vfu=0.63 (95% CI, 0.47-0.80). Bladder filling rate correlated with all thresholds (r=0.53 to 0.64, P<0.0001). Women with moderate to severe dysmenorrhea pain had increased bladder pain and urgency at Vfs and increased pain at Vfu (P's<0.05). In contrast, dysmenorrhea pain was unrelated to bladder capacity. DISCUSSION: Sonographic estimates of bladder sensory thresholds were reproducible and reliable. In these healthy volunteers, dysmenorrhea was associated with increased bladder pain and urgency during filling but unrelated to capacity. Plausibly, women with dysmenorrhea may exhibit enhanced visceral mechanosensitivity, increasing their risk to develop chronic bladder pain syndromes.

Interstitial cystitis in men.

Interstitial cystitis is an uncommon disease reported predominantly in females. Recently we were involved in the management of 4 men who had the clinical, endoscopic and pathological features consistent with the diagnosis of interstitial cystitis. The rarity of occurrence of the disease in males prompted us to report these cases.