Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis.
Interstitial cystitis (IC) is a debilitating disease that has been adversely affecting the quality of women's lives for many years. The trigger in IC is not entirely known, and a role for the sensory nerves in its pathogenesis has been suggested. In addition to inflammation, increased mast cell numbers in the detrusor muscle have been reported in a subset of IC patients. Experimentally, several lines of evidence support a central role for substance P and neurokinin-1 (NK-1) receptors in cystitis. The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R(-/-)) allows us to directly evaluate the importance of substance P in cystitis. An unexpected finding of this investigation is that NK-1R(-/-) mice present increased numbers of mast cells in the bladder when compared with wild-type control mice. Despite the increase in mast cell numbers, no concomitant inflammation was observed. In addition, bladder instillation of wild-type mice with a sensitizing antigen induces activation of mast cells and an acute inflammatory response characterized by plasma extravasation, edema, and migration of neutrophils. Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge. However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge. This work presents the first evidence of participation of NK-1 receptors in cystitis and a mandatory participation of these receptors on the chain of events linking mast cell degranulation and inflammation. (+info)
Urothelial pathophysiological changes in feline interstitial cystitis: a human model.
Unique barrier properties of the urothelial surface membrane permit urine storage. Interstitial cystitis causes disabling dysuria, and frequency. Similarly, feline interstitial cystitis (FIC) occurs in cats. These studies define the permeability and structural properties of normal and FIC urothelium. To determine the effects of bladder filling, groups were studied before and after hydrodistention. Normal urothelium with or without hydrodistention exhibited high transepithelial resistances (TER) and low water and urea permeabilities, resembling other species. Fluorescence confocal microscopy revealed localization of the marker AE-31 to the apical surface of all umbrella cells in normal urothelium, with the tight junction protein ZO-1 localized to tight junctions. Scanning and transmission electron microscopy revealed uniform distribution of luminal cells with characteristic apical membrane and tight junction morphology. Urothelium in FIC animals displayed reduced TER and increased water and urea permeability following hydrodistention. Structural studies in FIC revealed denuded urothelium, with appearance of AE-31 in underlying epithelial cells. The results demonstrate severe epithelial damage and dysfunction in FIC and suggest novel approaches toward examining the etiology and therapy of IC. (+info)
Interstitial cystitis: a retrospective analysis of treatment with pentosan polysulfate and follow-up patient survey.
To evaluate the efficacy and safety of pentosan polysulfate sodium (PPS) in relieving symptoms of interstitial cystitis, the authors retrospectively reviewed charts of 260 patients in whom interstitial cystitis had been diagnosed. Subsequently, they conducted a follow-up phone interview or mail survey of those patients who were treated with PPS to investigate changes in the patients' symptoms, adverse effects, and change in quality of life. The control group consisted of patients whose interstitial cystitis had been diagnosed at cystoscopy and had a duration of at least 1 year and who had taken at least one or more oral medications for their symptoms. The average length of treatment was 9.3 months among the 27 subjects on PPS therapy. The mean length of time that they had diagnosed interstitial cystitis was 35.63 months and 48.78 months for the PPS-treated and control groups, respectively, with no statistically significant difference. Changes in frequency, urgency, and pain were greater in the treatment group and statistically significant (P = .11, P = .49, and P = .004, respectively). No change occurred in the rate of nocturia in the PPS-treated group compared with that in the control group. Symptoms of both groups improved over time, but improvement was statistically significantly greater in the treatment group (P = .001) over the treatment interval. The most common side effect attributable to PPS was diarrhea in 15% of subjects. Pentosan proved to be an efficacious option for reducing the debilitating symptoms of interstitial cystitis. (+info)
Interstitial cystitis. Etiology, diagnosis, and treatment.
OBJECTIVE: To review current knowledge about the epidemiology, etiology, diagnosis, and treatment of interstitial cystitis, with special emphasis on management of this condition by family physicians. QUALITY OF EVIDENCE: Articles were identified through MEDLINE and review of abstracts presented at Urology and Interstitial Cystitis meetings during the last decade. Recent reviews were further searched for additional studies and trials. Data were summarized from large epidemiologic studies. Etiologic theories were extracted from current concepts and reviews of scientific studies. Diagnostic criteria described in this review are based on clinical interpretation of National Institutes of Health (NIH) research guidelines, interpretation of data from the NIH Interstitial Cystitis Cohort Study, and recent evidence on use of the potassium sensitivity test. Treatment suggestions are based on six randomized placebo-controlled clinical treatment trials and best available clinical data. MAIN MESSAGE: Interstitial cystitis affects about 0.01% to 0.5% of women. Its etiology is unknown, but might involve microbiologic, immunologic, mucosal, neurogenic, and other yet undefined agents. The diagnosis of interstitial cystitis is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, or hydroxyzine; and intravesical treatments with heparinlike medications, dimethyl sulfoxide, or BCG vaccine could benefit some patients. CONCLUSION: Family physicians should have an understanding of interstitial cystitis and be able to make a diagnosis and formulate an evidence-based treatment strategy for their patients. (+info)
Comorbid clinical conditions in chronic fatigue: a co-twin control study.
OBJECTIVES: Chronically fatiguing illness, defined as fatigue for at least 6 months, has been associated with various physical health conditions. Our objective was to determine whether there is a significant relationship between chronically fatiguing illness and 10 clinical conditions that frequently appear to be associated with fatigue, adjusting for the potentially confounding effects of psychiatric illness. DESIGN: A co-twin control study controlling for genetic and many environmental factors by comparing chronically fatigued twins with their nonfatigued co-twins. SETTING: A nationally distributed volunteer twin registry. PARTICIPANTS: The study included 127 twin pairs in which one member of the pair experienced fatigue of at least 6 months' duration and the co-twin was healthy and denied chronic fatigue. Fatigued twins were classified into 3 levels using increasingly stringent diagnostic criteria. MEASUREMENTS AND MAIN RESULTS: Twins reported on a history of fibromyalgia, irritable bowel syndrome, multiple chemical sensitivities, temporomandibular disorder, interstitial cystitis, postconcussion syndrome, tension headache, chronic low back pain, chronic pelvic pain (women), and chronic nonbacterial prostatitis (men). The prevalence of these comorbid clinical conditions was significantly higher in the fatigued twins compared to their nonfatigued co-twins. Most notably, compared to their nonfatigued co-twins, the chronically fatigued twins had higher rates of fibromyalgia (> 70% vs < 10%) and irritable bowel syndrome (> 50% vs < 5%). The strongest associations were observed between chronic fatigue and fibromyalgia (odds ratios > 20), irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivities, and temporomandibular disorder (all with odds ratios > or = 4). Regression analysis suggested that the number of comorbid clinical conditions associated with chronic fatigue could not be attributed solely to psychiatric illness. CONCLUSIONS: Chronically fatiguing illnesses were associated with high rates of many other clinical conditions. Thus, patients with chronic fatigue may present a complex clinical picture that poses diagnostic and management challenges. Nonetheless, clinicians should assess such patients for the presence of comorbid clinical conditions. Future research should provide a better understanding of the temporal relationship of the onset of fatigue and these conditions, and develop strategies for early intervention. (+info)
Interstitial cystitis: urgency and frequency syndrome.
Interstitial cystitis is a chronic, severely debilitating disease of the urinary bladder. Excessive urgency and frequency of urination, suprapubic pain, dyspareunia, chronic pelvic pain and negative urine cultures are characteristic of interstitial cystitis. The course of the disease is usually marked by flare-ups and remissions. Other conditions that should be ruled out include bacterial cystitis, urethritis, neoplasia, vaginitis and vulvar vestibulitis. Interstitial cystitis is diagnosed by cystoscopy and hydrodistention of the bladder. Glomerulations or Hunner's ulcers found at cystoscopy are diagnostic. Oral treatments of interstitial cystitis include pentosan polysulfate, tricyclic antidepressants and antihistamines. Intravesicular therapies include hydrodistention, dimethyl sulfoxide and heparin, or a combination of agents. Referral to a support group should be offered to all patients with interstitial cystitis. (+info)
A portuguese isolate of Borrelia lusitaniae induces disease in C3H/HeN mice.
A low-passage, Portuguese isolate of Borrelia lusitaniae, strain PotiB2, was inoculated into C3H/HeN mice and disease was monitored by histopathology at 8 weeks after spirochaete challenge. Ear, heart, bladder, femoro-tibial joint, brain and spinal cord were examined. B. lusitaniae strain PotiB2 (6 of 10 mice) and B. burgdorferi sensu stricto strain N40 (9 of 10 mice) induced similar lesions in the bladder of infected mice characterised as a multifocal, lymphoid, interstitial cystitis. Moreover, both B. lusitaniae PotiB2 and B. burdorferi N40 induced lesions in the heart of infected mice. The lesions induced by B. lusitaniae PotiB2 (2 of 10 mice) were characterised as a severe, necrotising endarteritis of the aorta, with a minimal, mixed inflammatory infiltrate (neutrophils, macrophages and lymphoid cells) extending into the adjacent myocardium. In contrast, B. burgdorferi N40 induced a periarteritis of the pulmonary artery (7 of 10 mice), with no involvement of the endothelium and more extensive inflammation and subsequent necrosis of the adjacent myocardium. This infiltrate was composed entirely of mononuclear cells, predominantly mature lymphocytes and plasma cells. No lesions were noted in the joints or central nervous system with inoculation of strains N40 or PotiB2, and co-inoculation of either strain with Ixodes ricinus salivary gland lysate did not affect the resulting pathology. Serology, examined 8 weeks after inoculation, indicated a different reactivity in mice infected with B. lusitaniae PotiB2 compared with B. burgdorferi N40. Immunoblot analysis demonstrated that mice with lesions resulting from infection with B. lusitaniae PotiB2 reacted only to the flagellin protein (41 kDa) or to flagellin and OspC, whereas mice infected with B. burgdorferi N40 reacted with multiple high and low mol. wt proteins, including flagellin, p93, p39, OspA, OspB and OspC. These results indicate that B. lusitaniae PotiB2 induced pathology similar to B. burgdorferi N40 when inoculated into susceptible mice. Moreover, these results establish the first animal model of disease with B. lusitaniae. This mouse model can be used to characterise the immunopathogenesis of B. lusitaniae infection and to delineate the proteins responsible for disease induction in susceptible mice. (+info)
Delayed toxicity of cyclophosphamide on the bladder of DBA/2 and C57BL/6 female mouse.
The present study describes the delayed development of a severe bladder pathology in a susceptible strain of mice (DBA/2) but not in a resistant strain (C57BL/6) when both were treated with a single 300 mg/kg dose of cyclophosphamide (CY). Inbred DBA/2 and C57BL/6 female mice were injected with CY, and the effect of the drug on the bladder was assessed during 100 days by light microscopy using different staining procedures, and after 30 days by conventional electron microscopy. Early CY toxicity caused a typical haemorrhagic cystitis in both strains that was completely repaired in about 7-10 days. After 30 days of CY injection ulcerous and non-ulcerous forms of chronic cystitis appeared in 86% of DBA/2 mice but only in 4% of C57BL/6 mice. Delayed cystitis was characterized by infiltration and transepithelial passage into the lumen of inflammatory cells and by frequent exfoliation of the urothelium. Mast cells appeared in the connective and muscular layers of the bladder at a much higher number in DBA/2 mice than in C57BL/6 mice or untreated controls. Electron microscopy disclosed the absence of the typical discoidal vesicles normally present in the cytoplasm of surface cells. Instead, numerous abnormal vesicles containing one or several dark granules were observed in the cytoplasm of cells from all the epithelial layers. Delayed cystitis still persisted in DBA/2 mice 100 days after treatment. These results indicate that delayed toxicity of CY in female DBA/2 mice causes a bladder pathology that is not observed in C57BL/6 mice. This pathology resembles interstitial cystitis in humans and could perhaps be used as an animal model for studies on the disease. (+info)