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European Journal of Histochemistry : EJH Mar 2021The urothelium, an epithelium of the urinary bladder, primarily functions as blood-urine permeability barrier. The urothelium has a very slow turn-over under normal... (Review)
Review
The urothelium, an epithelium of the urinary bladder, primarily functions as blood-urine permeability barrier. The urothelium has a very slow turn-over under normal conditions but is capable of extremely fast response to injury. During regeneration urothelium either restores normal function or undergoes altered differentiation pathways, the latter being the cause of several bladder diseases. In this review, we describe the structure of the apical plasma membrane that enables barrier function, the role of urothelium specific proteins uroplakins and the machinery for polarized membrane transports in terminally differentiated superficial umbrella cells. We address key markers, such as keratins, cancer stem cell markers, retinoic acid signalling pathway proteins and transient receptor potential channels and purinergic receptors that drive normal and altered differentiation in bladder cancer and bladder pain syndrome. Finally, we discuss uncertainties regarding research, diagnosis and treatment of bladder pain syndrome. Throughout the review, we emphasise the contribution of immunohistochemistry in advancing our understanding of processes in normal and diseased bladder as well as the most promising possibilities for improved bladder cancer and bladder pain syndrome management.
Topics: Animals; Cystitis, Interstitial; Humans; Immunohistochemistry; Receptors, Purinergic P2X; Transient Receptor Potential Channels; Urinary Bladder; Urinary Bladder Neoplasms; Uroplakins; Urothelium
PubMed: 33764020
DOI: 10.4081/ejh.2021.3242 -
BJOG : An International Journal of... Jan 2017To compare bladder sensitivity between patients with pelvic pain and patients who were pain free, undergoing noninvasive, controlled bladder distension via diuresis. We... (Observational Study)
Observational Study
OBJECTIVE
To compare bladder sensitivity between patients with pelvic pain and patients who were pain free, undergoing noninvasive, controlled bladder distension via diuresis. We also sought to measure potential mechanisms underlying bladder sensitivity.
DESIGN
Prospective observational study.
SETTING
Community teaching hospital.
POPULATION
Reproductive-age women with non-bladder chronic pelvic pain (CPP, n = 23), painful bladder syndrome (PBS, n = 23), and pelvic pain-free controls (n = 42) METHODS: Participants were compared on cystometric capacity, pelvic floor pressure-pain thresholds (PPTs), pelvic muscle function, O'Leary-Sant bladder questionnaire, and psychosocial instruments using Wilcoxon rank-sum tests. Multivariate regression was used to identify factors underlying bladder pain phenotypes.
MAIN OUTCOME MEASURES
Pelvic floor pain thresholds; self-reported bladder distension pain.
RESULTS
Participants with PBS exhibited higher bladder distension pain than those with CPP, with both groups reporting higher pain levels than controls (P < 0.05). No significant associations were found between bladder distension pain and pelvic muscle structure or pain sensitivity measures; however, bladder distension pain positively correlates with both vaginal PPTs adjacent to the bladder (r = 0.46) and pain with transvaginal bladder palpation (r = 0.56). Pain at maximal distension was less influenced by somatic sensitivity than bladder symptoms (r = 0.35 versus r = 0.59; P < 0.05). Multivariate regression identified three independent components of bladder symptoms in PBS: bladder distension pain, bladder sensation, and somatic symptoms.
CONCLUSIONS
Diuresis-induced bladder pain differentiates CPP from PBS. Experimental bladder pain is not predicted by pelvic floor sensitivity. Compared with patient-reported outcomes it appears less influenced by psychological factors. Further study is needed to determine whether screening for experimental bladder pain sensitivity could predict future risk of PBS.
TWEETABLE ABSTRACT
Controlled, water ingestion-provoked bladder pain can objectively identify visceral pain sensitivity.
Topics: Adult; Chronic Pain; Cystitis, Interstitial; Diuresis; Female; Humans; Multivariate Analysis; Pain Measurement; Pain Threshold; Pelvic Floor; Pelvic Pain; Pressure; Prospective Studies; Regression Analysis; Statistics, Nonparametric; Surveys and Questionnaires; Urinary Bladder; Young Adult
PubMed: 28012262
DOI: 10.1111/1471-0528.14433 -
International Journal of Environmental... Oct 2023Clinical guidelines developed by urologic, urogynecologic, and gynecologic associations around the globe include recommendations on nutrition-related lifestyle and... (Review)
Review
BACKGROUND
Clinical guidelines developed by urologic, urogynecologic, and gynecologic associations around the globe include recommendations on nutrition-related lifestyle and behavioral change for bladder storage conditions. This study identified and compared clinical guidelines on three urological conditions (interstitial cystitis/bladder pain syndrome (IC/BPS), overactive bladder, and stress urinary incontinence) affecting adult women.
METHODS
A three-step process was employed to identify the guidelines. Next, a quality assessment of the guidelines was conducted employing the Appraisal of Guidelines Research and Evaluation (AGREE II) International tool. (3) Results: Twenty-two clinical guidelines, prepared by seventeen groups spanning four continents, met the inclusion criteria. The AGREE II analyses revealed that most of the guideline development processes complied with best practices. The most extensive nutrition recommendations were for women with IC/BPS. Dietary manipulation for the other two storage LUTS primarily focused on the restriction or limitation of specific beverages and/or optimal fluid intake. (4) Conclusion: Clinical guidelines for IC/BPS, overactive bladder, and stress urinary incontinence include nutrition recommendations; however, the extent of dietary manipulation varied by condition. The need to ensure that clinicians are informing patients of the limitations of the evidence supporting those recommendations emerged. Furthermore, given the need to treat nutrition-related comorbid conditions as a strategy to help mitigate these three urological disorders, the value of referral to a dietitian for medical nutrition therapy is apparent.
Topics: Female; Humans; Adult; Urinary Bladder; Urinary Bladder, Overactive; Urinary Incontinence, Stress; Cystitis, Interstitial; Severity of Illness Index
PubMed: 37835149
DOI: 10.3390/ijerph20196879 -
International Journal of Molecular... Dec 2021The cation channel TRPM3 is activated by heat and the neurosteroid pregnenolone sulfate. TRPM3 is expressed on sensory neurons innervating the skin, where together with...
The cation channel TRPM3 is activated by heat and the neurosteroid pregnenolone sulfate. TRPM3 is expressed on sensory neurons innervating the skin, where together with TRPV1 and TRPA1, it functions as one of three redundant sensors of acute heat. Moreover, functional upregulation of TRPM3 during inflammation contributes to heat hyperalgesia. The role of TRPM3 in sensory neurons innervating internal organs such as the bladder is currently unclear. Here, using retrograde labeling and single-molecule fluorescent RNA in situ hybridization, we demonstrate expression of mRNA encoding TRPM3 in a large subset of dorsal root ganglion (DRG) neurons innervating the mouse bladder, and confirm TRPM3 channel functionality in these neurons using Fura-2-based calcium imaging. After induction of cystitis by injection of cyclophosphamide, we observed a robust increase of the functional responses to agonists of TRPM3, TRPV1, and TRPA1 in bladder-innervating DRG neurons. Cystometry and voided spot analysis in control and cyclophosphamide-treated animals did not reveal differences between wild type and TRPM3-deficient mice, indicating that TRPM3 is not critical for normal voiding. We conclude that TRPM3 is functionally expressed in a large proportion of sensory bladder afferent, but its role in bladder sensation remains to be established.
Topics: Animals; Cyclophosphamide; Cystitis; Female; Ganglia, Spinal; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Neurons, Afferent; Pregnenolone; RNA, Messenger; TRPA1 Cation Channel; TRPM Cation Channels; TRPV Cation Channels; Up-Regulation; Urinary Bladder
PubMed: 35008533
DOI: 10.3390/ijms23010107 -
Hong Kong Medical Journal = Xianggang... Dec 2022This systematic review and meta-analysis focused on the literature regarding ketamine-associated uropathy to summarise its clinical manifestations, the results of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
This systematic review and meta-analysis focused on the literature regarding ketamine-associated uropathy to summarise its clinical manifestations, the results of urological assessments, and current management.
METHODS
A literature search was conducted using keywords and MeSH terms related to ketamine abuse, urinary tracts, and urological examinations. Databases including Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched up to 26 June 2020.
RESULTS
In total, 1365 articles were retrieved; 45 articles (4921 patients) were included in the analysis of patient demographics, clinical manifestations, examination results, and treatments. Frequency was the most common manifestation (pooled prevalence 77.1%, 95% confidence interval [CI]=56.9%-92.2%), followed by urgency (69.9%, 95% CI=48.8%-87.3%) and suprapubic pain (60.4%, 95% CI=35.3%-82.9%). Upper urinary tract involvement was less common; the pooled prevalence of hydronephrosis was 30.2% (95% CI=22.0%-39.2%). Further workup revealed a pooled functional bladder capacity of 95.23 mL (95% CI=63.57-126.88 mL), pooled voided volume of 113.31 mL (95% CI=59.44- 167.19 mL), and pooled maximum urine flow rate of 8.69 mL/s (95% CI=5.54-11.83 mL/s). Cystoscopic examinations and bladder biopsy revealed frequent urothelial denudation, inflammatory changes, and inflammatory cell infiltration. Treatments included oral medications for symptomatic relief, intravesical therapy, and surgery (eg, hydrodistension and bladder reconstruction), but ketamine abstinence was necessary for improvement.
CONCLUSION
Ketamine-associated uropathy frequently involves frequency, urgency, and suprapubic pain; upper urinary tract involvement is less common. Affected patients showed reductions in bladder capacity and urine flow rate. Endoscopic and histological analyses often revealed cystitis. Despite variations in treatment, ketamine abstinence is important for all patients with ketamine-associated uropathy.
Topics: Humans; Ketamine; Cystitis; Urologic Diseases; Urinary Bladder; Pain
PubMed: 36464318
DOI: 10.12809/hkmj209194 -
Stem Cell Reviews and Reports Feb 2020Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue... (Review)
Review
Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue regeneration. Mesenchymal stem cells are multipotent progenitor cells with enhanced proliferation and differentiation capabilities and less tumorigenicity than conventional adult stem cells; these cells are also easier to acquire. Bladder dysfunction is often chronic in nature with limited treatment modalities due to its undetermined pathophysiology. Most treatments focus on symptom alleviation rather than pathognomonic changes repair. The potential of stem cell therapy for bladder dysfunction has been reported in preclinical models for stress urinary incontinence, overactive bladder, detrusor underactivity, and interstitial cystitis/bladder pain syndrome. Despite these findings, however, stem cell therapy is not yet available for clinical use. Only one pilot study on detrusor underactivity and a handful of clinical trials on stress urinary incontinence have reported the effects of stem cell treatment. This limitation may be due to stem cell function loss following ex vivo expansion, poor in vivo engraftment or survival after transplantation, or a lack of understanding of the precise mechanisms of action underlying therapeutic outcomes and in vivo behavior of stem cells administered to target organs. Efficacy comparisons with existing treatment modalities are also needed for the successful clinical application of stem cell therapies. This review describes the current status of stem cell research on treating bladder dysfunction and suggests future directions to facilitate clinical applications of this promising treatment modality, particularly for bladder dysfunction.
Topics: Cell Self Renewal; Cell- and Tissue-Based Therapy; Chemokines; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Regeneration; Urinary Bladder; Urinary Bladder Diseases; Urinary Incontinence, Stress
PubMed: 31758372
DOI: 10.1007/s12015-019-09922-2 -
BioMed Research International 2014Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder related and with... (Review)
Review
Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder related and with at least one urinary symptom. It was recently concluded that 3.3-7.9 million women (>18 years old) in the United States exhibit BPS/IC symptoms. The impact of BPS/IC on quality of life is enormous and the economic burden is significant. Although the etiology and pathogenesis of BPS/IC are unknown, numerous theories including infection, inflammation, autoimmune disorder, toxic urinary agents, urothelial dysfunction, and neurogenic causes have been proposed. Altered visceral sensations from the urinary bladder (i.e., pain at low or moderate bladder filling) that accompany BPS/IC may be mediated by many factors including changes in the properties of peripheral bladder afferent pathways such that bladder afferent neurons respond in an exaggerated manner to normally innocuous stimuli (allodynia). The goals for this review are to describe chemokine/receptor (CXCL12/CXCR4; CCL2/CCR2) signaling and cytokine/receptor (transforming growth factor (TGF-β)/TGF-β type 1 receptor) signaling that may be valuable LUT targets for pharmacologic therapy to improve urinary bladder function and reduce somatic sensitivity associated with urinary bladder inflammation.
Topics: Chemokines; Cytokines; Humans; Inflammation; Receptors, Chemokine; Receptors, Cytokine; Signal Transduction; Urinary Bladder
PubMed: 24738044
DOI: 10.1155/2014/120525 -
BMC Urology Oct 2021Baclofen, a clinically available GABA receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder...
BACKGROUND
Baclofen, a clinically available GABA receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception.
METHODS
A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity.
RESULTS
Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABA receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABA activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed.
CONCLUSIONS
These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.
Topics: Animals; Baclofen; Female; GABA-B Receptor Agonists; Injections, Spinal; Nociception; Rats; Rats, Sprague-Dawley; Urinary Bladder
PubMed: 34607587
DOI: 10.1186/s12894-021-00899-0 -
Female Pelvic Medicine & Reconstructive... Sep 2021Interstitial cystitis/bladder pain syndrome (IC/BPS) comprises at least 2 phenotypes. Bladder centric patients typically demonstrate low bladder capacity (BC), often...
OBJECTIVES
Interstitial cystitis/bladder pain syndrome (IC/BPS) comprises at least 2 phenotypes. Bladder centric patients typically demonstrate low bladder capacity (BC), often with Hunner lesion (HL), whereas non-bladder-centric patients typically have normal cystoscopic findings and more co-occurring nonurologic symptoms/syndromes (NUS), contributing to widespread pain beyond the bladder. Small fiber polyneuropathy (SFPN) is significantly associated with fibromyalgia, a frequent IC/BPS codiagnosis and may play an etiologic role in IC/BPS. We assessed SFPN status in bladder-centric versus non-bladder-centric IC/BPS patients.
METHODS
Distal leg biopsies were obtained from 11 IC/BPS patients after therapeutic hydrodistention. Specimens were embedded/sectioned per standard protocol and stained for protein gene product 9.5, an intraepidermal nerve fiber marker. To determine SFPN status, intraepidermal nerve fiber density was calculated and compared with normative reference values stratified by age/sex. The SFPN prevalence and reported comorbidities were compared between low BC and/or HL-positive (bladder-centric) versus non-low BC, HL (non-bladder-centric) patients.
RESULTS
Seven patients (63.6%) were SFPN positive. Non-bladder-centric patients demonstrated significantly more SFPN (6/7, 85.7%) compared with bladder-centric patients (1/4, 25.0%; P = 0.027). Non-bladder-centric patients also reported more comorbid NUS overall (1.25 ± 0.83 vs 5.86 ± 2.47; P = 0.003), including fibromyalgia (P = 0.010), migraines (P = 0.035), anxiety/panic disorder (P = 0.035), allergies (P = 0.027), and asthma (P = 0.035).
CONCLUSIONS
In this pilot study, SFPN was significantly more common in non-bladder-centric IC/BPS, that is, those patients who also reported greater prevalence of NUS, including fibromyalgia, migraines, anxiety/panic disorders, allergies, and asthma. These findings suggest that SFPN may have an etiologic role in a larger, systemic pain syndrome and should be explored further.
Topics: Cystitis, Interstitial; Humans; Pain; Pilot Projects; Polyneuropathies; Urinary Bladder
PubMed: 33109931
DOI: 10.1097/SPV.0000000000000972 -
Current Topics in Membranes 2022Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a urologic, chronic pelvic pain syndrome characterized by pelvic pain, pressure, or discomfort with urinary... (Review)
Review
Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a urologic, chronic pelvic pain syndrome characterized by pelvic pain, pressure, or discomfort with urinary symptoms. Symptom exacerbation (flare) is common with multiple, perceived triggers including stress. Multiple transient receptor potential (TRP) channels (TRPA1, TRPV1, TRPV4) expressed in the bladder have specific tissue distributions in the lower urinary tract (LUT) and are implicated in bladder disorders including overactive bladder (OAB) and BPS/IC. TRPV4 channels are strong candidates for mechanosensors in the urinary bladder and TRPV4 antagonists are promising therapeutic agents for OAB. In this perspective piece, we address the current knowledge of TRPV4 distribution and function in the LUT and its plasticity with injury or disease with an emphasis on BPS/IC. We review our studies that extend the knowledge of TRPV4 in urinary bladder function by focusing on (i) TRPV4 involvement in voiding dysfunction, pelvic pain, and non-voiding bladder contractions in NGF-OE mice; (ii) distention-induced luminal ATP release mechanisms and (iii) involvement of TRPV4 and vesicular release mechanisms. Finally, we review our lamina propria studies in postnatal rat studies that demonstrate: (i) the predominance of the TRPV4+ and PDGFRα+ lamina propria cellular network in early postnatal rats; (ii) the ability of exogenous mediators (i.e., ATP, TRPV4 agonist) to activate and increase the number of lamina propria cells exhibiting active Ca events; and (iii) the ability of ATP and TRPV4 agonist to increase the rate of integrated Ca activity corresponding to coupled lamina propria network events and the formation of propagating wavefronts.
Topics: Adenosine Triphosphate; Animals; Mice; Nerve Growth Factor; Pelvic Pain; Rats; Receptor, Platelet-Derived Growth Factor alpha; TRPV Cation Channels; Transient Receptor Potential Channels; Urinary Bladder; Urinary Bladder, Overactive
PubMed: 36210154
DOI: 10.1016/bs.ctm.2022.06.002