This Month in Investigative Urology

Article Outline

• Melatonin Increases Bladder Capacity and Decreases Urine Volume
• Gli2 Expression and Bladder Transitional Carcinoma Cell Invasiveness
• Nanobacteria: A Possible Etiology for Type III Prostatitis
• Antibiofilm Effect of Trans-Cinnamaldehyde on Uropathogenic Escherichia coli
• Morphological Expression of KIT Positive Interstitial Cells of Cajal in the Bladder
• Copyright

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Melatonin Increases Bladder Capacity and Decreases Urine Volume 

Nocturia is a common disorder that increases with age, possibly due to decreased functional bladder capacity, nocturnal polyuria and sleep disturbance. In older adults the secretion of melatonin, which is predominant at night, is impaired, which may lead to disruption of the normal circadian pattern of sleep and nocturia. Matsuta et al (page 386) from Fukui, Japan hypothesized that melatonin could alleviate urinary frequency via suppression of the micturition center in the brain, and investigated the central contribution of melatonin to bladder function and urine volume in female rats. Intracerebroventricular melatonin alone or with the γ-aminobutyric acid_A antagonist bicuculline was administered and the effects on bladder function were examined by cystometry.

Melatonin significantly increased bladder capacity dose dependently but had no significant effect on bladder contraction pressure. Bicuculline inhibited the melatonin induced increases in bladder capacity. Melatonin decreased urine volume in water loaded rats but plasma antidiuretic hormone, atrial natriuretic peptide and brain natriuretic peptide levels were unchanged 4 hours after melatonin administration. The authors conclude that melatonin can increase bladder capacity and reduce urine volume in rats via a γ-aminobutyric acid_A receptor mechanism in the brain. Thus, they speculate that melatonin could be beneficial for treatment of nocturia in humans.

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Gli2 Expression and Bladder Transitional Carcinoma Cell Invasiveness 

The genetic aspects that regulate tumor cell invasion are of primary concern for bladder cancer research. Hedgehog (Hh) signaling regulates Gli transcription factors and aberrant Hh signaling can be oncogenic. Mechlin et al (page 344) from Albany, New York studied whether Hh/Gli signaling is involved in proliferative or invasive behavior of human bladder transitional cell carcinoma (TCC). Human bladder TCC lines RT4, 253JP, 253BV, UMUC6 and UMUC3 were stratified for relative growth rate and for in vitro invasiveness. Cell growth inhibition was tested by the Hh blocking drug cyclopamine or the inactive mimic tomatadine, and cell RNA was characterized for expression of Hh signaling components by quantitative reverse transcriptase-polymerase chain reaction. Gli2 expression or activity was modified using Gli2 expression lentiviruses or the Gli-inhibitor GANT61, and the effects on proliferation and invasiveness were measured.

All cells were weakly growth inhibited by tomatadine and cyclopamine. Gli2 was the only Hh signaling molecule whose expression correlated with the stratification. Manipulation of Gli2 expression or activity significantly affected the invasiveness of these cells. The authors conclude that Hh signaling is not involved in bladder cancer cell proliferation. However, Gli2 expression strongly correlated with invasive behavior. The authors further suggest that considerations of Hh inhibitory strategies for bladder cancer should focus on targeting Gli rather than upstream aspects of Hh signaling.

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Nanobacteria: A Possible Etiology for Type III Prostatitis 

The etiology of type III chronic prostatitis remains unclear and potential infectious pathogens are unknown. Nanobacteria are thought to be associated with its pathogenesis. Shen et al (page 364) studied the pathological changes of nanobacteria infected prostates in Sprague-Dawley® rats, and the possible etiological relationship between nanobacteria and type III prostatitis. Rats were sacrificed 1, 2, 4 and 8 weeks after transurethral nanobacteria infusion. Prostate pathology, and the cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α were assessed. Nanobacteria isolation, culture and characterization were also analyzed.

There were acute inflammatory changes in treated prostates 1 to 2 weeks after infusion and chronic inflammatory changes after 4 weeks. After 8 weeks there was microcalculi formation in the prostatic glandular cavity in 7 of the 10 rats in the nanobacteria group and none in the control group. IL-1β and TNF-α in prostatic tissues were greater in the nanobacteria group than in the control group at different time points. IL-1β and TNF-α were greater at 2 weeks than at 1, 4 and 8 weeks after nanobacteria infusion. The authors provide a new approach for the etiological study of type III prostatitis and conclude that nanobacteria may be an important etiological factor for this disease.

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Antibiofilm Effect of Trans-Cinnamaldehyde on Uropathogenic Escherichia coli 

Catheter associated urinary tract infections account for an estimated 150 million cases per year worldwide and are caused primarily by uropathogenic Escherichia coli (UPEC). Indwelling urinary catheters for bladder drainage become encrusted with UPEC biofilms that are resistant to common antibiotics, resulting in chronic infections. Effective strategies are needed to prevent UPEC biofilm on catheters and a variety of plant derived polyphenols have been suggested. Amalaradjou et al (page 358) from Glastonbury, Connecticut investigated the efficacy of trans-cinnamaldehyde (TC), the principle component in cinnamon oil, in the prevention of UPEC biofilm and the inactivation of preformed UPEC biofilm.

Polystyrene plates and urinary catheters inoculated with UPEC were treated with TC at 37C. Additionally, catheters with UPEC biofilm were treated with lock solution containing TC. UPEC biofilm on control and TC treated plates and catheters was determined on days 0, 1, 3 and 5 of incubation. In addition, the potential cytotoxity of TC was determined on HTB-4 bladder epithelial cells. All TC concentrations were effective in preventing UPEC biofilm on plates and catheters. Furthermore, as a constituent in catheter lock solution, TC inactivated UPEC biofilm on catheters. TC produced no cytotoxic effects on human bladder epithelial cells at the tested concentrations. The authors conclude that TC could be applied as a coating on catheter surface or an ingredient in catheter lock solution to prevent urinary tract infections.

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Morphological Expression of KIT Positive Interstitial Cells of Cajal in the Bladder 

Interstitial cells of Cajal (ICC) in the bladder have a putative association with bladder pathophysiology such as detrusor overactivity and the overactive bladder syndrome. Over expression of ICC may generate aberrant contractility, and there is evidence that these cells are present in normal bladder and have physiological profiles consistent with modulatory functions. Johnston et al (page 370) from Belfast, United Kingdom investigated the 3-dimensional morphological arrangement of KIT positive ICC in human bladder biopsy samples and explored the structural interactions with neighboring cells.

Whole mount, flat sheet preparations labeled with anti-KIT contained several populations of immunopositive ICC. A network of stellate ICC was present in the lamina propria and made structural connections with a cholinergic nerve plexus. Vimentin positive cells of several morphologies were present in the lamina propria, presumably including fibroblasts, ICC and other cells of mesenchymal origin. Microvessels were abundant in this region and branched, elongated KIT positive ICC were found discretely along the vessel axis. Detrusor ICC were spindle-shaped, branched cells tracking the smooth muscle bundles, closely associated with smooth muscle cells and cholinergic nerves. Transmission electron microscopy revealed cells with the ultrastructural characteristics of ICC throughout the human bladder wall. The authors conclude that human bladder contains a network of KIT positive ICC in the lamina propria, which make frequent connections with a cholinergic nerve plexus. Perivascular ICC were found close to vascular smooth muscle cells, suggesting ICC-vascular coupling in the bladder. The KIT positive detrusor ICC, smooth muscle bundles and nearby nerves may constitute a functional tri-unit controlling bladder contractility.