Search

Purpose: Interstitial cystitis is a painful bladder disease characterized by urgency, frequency and variable inflammation but there is no curative therapy. Suplatast tosilate (IPD-1151T) is an immunoregulatory compound that decreases interstitial cystitis symptoms but to our knowledge its mechanism of action is unknown. We investigated the effect of intravesical IPD-1151T on mediator release from bladder explants in experimental cystitis., Materials and Methods: A catheter was inserted into the bladder of female mice. After urine was emptied normal saline, carbachol (100 nM) or lipopolysaccharide (10 mg/ml) was introduced with or without 10-minute pretreatment with IPD-1151T. Urine was removed after 45 minutes for histamine and tumor necrosis factor-alpha assays. The bladder was removed after 4 hours, minced into 1 mm2 pieces and cultured with or without triggers overnight for mediator release. The effect of IPD-1151T was also tested on rat skin vascular permeability as well as on purified rat peritoneal mast cells and human cord blood derived mast cells., Results: Carbachol significantly increased histamine release in urine (61.3% in 8 preparations, p<0.05) but not in explant medium. IPD-1151T inhibited this effect by 77%. Lipopolysaccharide induced a 350% urine histamine increase in 9 preparations (p<0.05) and a 300% tumor necrosis factor-alpha increase in explant medium. IPD-1151T inhibited the lipopolysaccharide induced medium tumor necrosis factor-alpha increase by 95% in 5 preparations (p<0.05). IPD-1151T did not inhibit rat skin vascular permeability or purified rat peritoneal mast cell activation by compound 48/80 or human cord blood derived mast cells by anti-IgE., Conclusions: IPD-1151T inhibits bladder release of histamine and tumor necrosis factor-alpha through a mechanism that does not appear to involve direct mast cell inhibition. These findings may justify a beneficial effect of IPD-1151T in interstitial cystitis.

Purpose: We established whether the urinary cytokines interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha and soluble TNF receptor-1 have a role as noninvasive markers of renal damage in children with vesicoureteral reflux., Materials and Methods: We performed an observational study in a surgical and urological unit at a pediatric teaching hospital. Urine cytokine levels of IL-6, TNF-alpha and soluble TNF receptor-1 were measured using a standard enzyme-linked immunosorbent assay technique in children stratified into group 1--11 with vesicoureteral reflux and reflux nephropathy, group 2--6 with vesicoureteral reflux only and no associated nephropathy, and group 3--15 age and sex matched controls., Results: Urinary levels of the cytokines IL-6 and soluble TNF receptor-1 were significantly elevated in group 1 versus group 3 (0.048 to 13.25 pg./micromol. creatinine, mean 3.658 versus 0.027 to 0.677, mean 0.247 and 102.89 to 4,502.9 pg./micromol. creatinine, mean 1,395.3 versus 13.06 to 569.6, mean 145.357, respectively). Neither cytokine in group 2 (0.074 to 10.96 pg./micromol. creatinine, mean 2.94 and 51.52 to 1,115.48, mean 413.137, respectively) was elevated compared to that in group 3. TNF-alpha was not elevated in group 1 or 2 compared to that in group 3 (0.104 to 2.518 pg./micromol. creatinine, mean 0.56, 0.094 to 1.278, mean 0.334 and 0.065 to 0.694, mean 0.241, respectively)., Conclusions: Measuring the urinary levels of the cytokines IL-6 and soluble TNF receptor-1 may be useful as a noninvasive marker of reflux associated renal damage. Further studies with larger patient groups are necessary to locate the source of production of the elevated urinary cytokines measured in our study.

Purpose: The goal of this research was to discover new biological indicators in urine which could be used for short-term prognosis of local Bacillus Calmette-Guerin (BCG) therapy outcome in patients with superficial bladder cancer., Patients and Methods: We measured and statistically evaluated soluble immunological molecules in urine from bladder cancer patients (n = 34) receiving BCG intravesically. Urine was collected following each of 6 weekly treatments, processed and assayed. The data base included measurements of interleukin-1 (IL-2, IL-4, IL-6, IL-10, IL-12, soluble intercellular adhesion molecule-1 (sICAM-1), tumour necrosis factor-alpha (TNF alpha), soluble CD14 (sCD14), interferon-gamma (IFN gamma), GM-CSF, volume of urine and its pH. The clinical response was evaluated by urine histology and random quadrant biopsy 3 months after the start of therapy. Patients were divided into 2 groups, with good and poor therapeutic effect. The initial complete response rate was 62% (21/34). The data base was analyzed using traditional multivariate statistical methods and a pattern recognition method which deals with combinatorial-statistical analysis (statistically weighted syndromes (SWS) method) of the gradated features. The SWS method is capable of identifying robust patterns in small "fuzzy" sets with high dimensional objects and some missing values., Results: Only one parameter gave significant differences at p < 0.05, GM-CSF at instillation 6. Repeated measurement analysis of variance, backward stepwise multiple logistic regression and linear discriminant analysis failed to show any significance. However, significant differences in the structure of correlation between features in the groups with and without therapeutic effect were observed and four highly informative variables (the masses of sICAM-1, TNF alpha, sCD14 and pH) relating to 5th-6th installations were selected by SWS. These features provided accurate individual prediction of therapeutic outcome for all our patients. Cross-validation analysis and computer simulation showed the statistically significant stability of the prediction., Conclusion: We have selected a set of urinary variables that could be considered as a perspective combination of indicators (syndromes) of outcome of pre-operation BCG therapy of patients with superficial bladder cancer. A larger patient database will provide testing and evaluation of the biological and clinical significance of selected features. The computational syndrome-disease approach should be applicable for the solution of decision-making problems for management of cancer.

Interstitial cystitis is a syndrome of urinary urgency, frequency and suprapubic pain. We investigated the role of inflammatory mediators in 96 patients with histories and symptoms consistent with interstitial cystitis, and 13 controls from The New York Hospital-Cornell Medical Center, University of Washington and University of California at San Diego. Patients were classified into either group A (meets all criteria of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases for inclusion in research studies), group B (meets all of these criteria but without glomerulations) or an "other" group. A small number of group A patients had detectable interleukin-6 in the urine. Urinary concentrations of tumor necrosis factor, prostaglandins E2, D2 and F2 alpha, and thromboxane B2 were not different among either patient groups or controls. Urine specimens contained inhibitors of the bioactivity of interleukin-6 and tumor necrosis factors but no differences between patients or controls were found. No factors chemotactic for human neutrophils were detected in a small patient sample. Bladder wash fluid concentrations of prostaglandins E2, D2 and F2 alpha, and thromboxane were much lower than urinary levels. Bladder wash fluid interleukin-6 and tumor necrosis factor were not detectable. The results suggest that while a small subset of patients may have elevated levels of interleukin-6 the majority of patients do not appear to have elevated levels of inflammatory mediators in the urine or bladder wash fluid. Evaluation of patient bladder tissue may indicate changes not detectable in urine or bladder wash fluid. Alternatively, other etiologies must be considered in those patients.

In an attempt to elucidate further the immunological mechanisms responsible for the effectiveness of intravesical bacillus Calmette-Guerin in the therapy of superficial urothelial bladder cancer, a prospective study was performed in which the urine of patients was examined before and after 6 intravesical instillations of bacillus Calmette-Guerin for the presence of the cytokines interleukin-1, interleukin-2 and tumor necrosis factor-alpha. Biological assays such as specific sandwich enzyme-linked immunosorbent assays were used for the analysis of each cytokine. Urinary titers of interleukin-1, interleukin-2 and tumor necrosis factor increased significantly after bacillus Calmette-Guerin instillation but showed inter-individual differences. The maximum of secretion into the urine was seen between 4 and 8 hours after the instillation, and titers returned to baseline values within 24 hours. The differences in 24-hour secretion between the bacillus Calmette-Guerin-treated (10 patients) and the control (10) groups were significant with respect to all cytokines as tested in both assays each, except for the interleukin-1 biological assay. These results reflect the strong inflammatory response in the bladder wall to bacillus Calmette-Guerin, in which the urinary secretion of the detected cytokines may be associated with the local tumor control.