Increasing use of abdominal imaging is increasing the incidence of asymptomatic renal masses and small renal masses (less than 4 cm) currently account for 48% to 66% of all renal cell carcinomas. The standard of care for clinically localized renal cell carcinoma remains surgical resection but ablative therapy may be a good compromise for small renal masses in elderly patients with significant comorbidities. As cryotherapy is a new modality of treatment there are few standards and many questions about efficacious application. Preoperative planning for renal cryotherapy is based on isotherms established in gel. Young et al (page 752) from Orange, California replicated and correlated the gel isotherms with ex vivo and in vivo isotherms in a porcine model. They investigated 1.7 mm PERC-17 CryoProbes™ and 1.47 mm IceRods™ in gel, ex vivo and in vivo porcine kidneys, and recorded temperatures at 13 predetermined locations with thermal sensors.
Temperatures at the cryoprobe were not significantly different along the probe in any media for either system. However, away from the probe ex vivo and in vivo trials revealed warmer temperatures toward the cryoprobe tip for both systems. Mean temperature 5 mm distal to the tip of the cryoprobe in vivo was 19.2C (SE 16.1) for CryoProbes and 27.3C (SE 11.2) for IceRods. Temperatures were consistently colder with CryoProbes than IceRods in gel, ex vivo and in vivo kidneys, and temperatures were significantly colder in gel and ex vivo kidneys than in in vivo kidneys at nearly all sites. The authors conclude that gel and ex vivo isotherms are not predictive of the in vivo pattern of freezing and, thus, should not be used for preoperative planning. The cryoprobe should be passed 5 mm beyond the tumor border to achieve suitably cold temperatures. Thermal sensors are recommended to record the actual temperature during renal cryotherapy.
Next Generation Biodegradable Ureteral Stent
Ureteral stents are commonly used in urology to facilitate kidney drainage. However, stents that remain indwelling for longer periods are more prone to infection and encrustation, and forgotten stents can lead to renal failure or death. A biodegradable stent would eliminate the problem of forgotten stents. Previous biodegradable stents have shown bio-incompatibility and inconsistent degradation requiring extra procedures to remove undegraded stent fragments.
Having previously reported on a first generation biodegradable stent composed of suture-like material, which required placement through the lumen of a sheath and degraded by 10 weeks, Chew et al (page 765) from Vancouver, Canada describe their experience with second and third generation biodegradable stents, which degrade more rapidly than those of the first generation and can be placed directly over a polytetrafluoroethylene guide wire. They investigated 2 groups of 16 Yucatan pigs, which were unilaterally stented endoscopically with a control nondegradable (biostable) stent or a second generation degradable Uriprene® stent. Bloodwork, renal ultrasounds and intravenous pyelograms were obtained to determine renal function, hydronephrosis and stent degradation. Genitourinary organs were harvested at necropsy for pathological analysis. A third generation stent designed to improve degradation time was implanted bilaterally endoscopically in 4 Yorkshire Farm pigs (8 stents), and followed by weekly excretory urography to examine degradation and kidney function. Biomaterial parameters were tested.
Second generation stents began degrading at 2 weeks and were completely degraded by 10 weeks. All third generation stents were degraded by 4 weeks. Hydronephrosis was considerably less in the Uriprene group compared to control kidneys. On average, biostable stented ureters demonstrated a higher degree of inflammation, uropathy and nephropathy. The physical characteristics indicate that Uriprene stents are significantly more resistant to stent compression, demonstrate a markedly higher tensile strength and have a coil strength comparable to other commercially available plastic stents. The authors conclude that Uriprene ureteral stents hold promise in decreasing the need for a secondary procedure but future studies will be required to assess whether they decrease stent related morbidity such as infection, irritative symptoms and encrustation.
Effects of Adenosine Triphosphate on Contractile and Pacemaker Activity in Urethral Smooth Muscle
Urinary continence depends on the ability of the urethra to generate closure pressure that exceeds intravesical pressure in the bladder. A key factor in this process is the ability of urethral smooth muscle to generate spontaneous tone. The level of tone is regulated by several neurotransmitters, including noradrenaline, acetylcholine and nitric oxide. Adenosine triphosphate (ATP) is also an important urethral neurotransmitter but its physiological role is still unclear. To characterize the effects of ATP on contractile and pacemaker activity in rabbit urethral smooth muscle Bradley et al (page 801) from County Louthe, Ireland made tension recordings from strips of rabbit proximal urethra smooth muscle, recorded membrane currents from freshly isolated smooth muscle cells and interstitial cells of Cajal (ICC) using the patch clamp technique, and measured intracellular Ca2+ using confocal microscopy.
Exogenous application of ATP evoked robust contractions that were inhibited by the type 2 purinergic (P2) receptor blocker suramin and the selective P2Y1 receptor antagonist MRS2500. Application of the P2Y receptor agonist 2 methylthio adenosine diphosphate (2-MeSADP) mimicked the effects of ATP. When smooth muscle cells were studied under voltage clamp at –60 mV, ATP evoked a large single inward current (greater than 1.2 nA), whereas 2-MeSADP produced a small current (approximately 16 pA). In contrast, when ICC were held at –60 mV they exhibited spontaneous transient inward currents that were increased in frequency by ATP and 2-MeSADP. These excitatory effects were inhibited by suramin and MRS2500. ICC developed spontaneous Ca2+ waves that were increased in frequency by ATP and 2-MeSADP. These effects were also inhibited by suramin and MRS2500. The authors conclude that ATP is an excitatory neurotransmitter in rabbit urethral smooth muscle that may mediate the muscle effects by regulating the frequency of pacemaker activity in ICC by activation of P2Y receptors.
Visualization and Tissue Distribution of the α1L-Adrenoceptor by Alexa-488-Silodosin
α1-Adrenoceptor (AR) antagonists are a first line treatment for lower urinary tract symptoms associated with benign prostate hyperplasia. In addition to the 3 cloned subtypes of α1-AR (α1A, α1B, and α1D), another α1-AR with low affinity for prazosin, α1L-AR, has been identified in various tissues and organs including the prostate. α1L-AR is now considered another phenotype, sharing the α1A-AR gene and protein molecule. However, the most common techniques, such as immunohistochemistry and in situ hybridization, are not applicable for examining the tissue distribution of the α1L-AR and distinguishing its expression from α1A-AR expression, because the α1L subtype can only be successfully detected when the receptor environment is conserved and not perturbed by homogenization. Morishima et al (page 812) from Fukui, Japan labeled silodosin, an α1A and α1L-adrenoceptor selective antagonist, with the fluorophore Alexa Fluor 488® (Alexa-488-silodosin) to visualize α1L-AR expression. Radioligand binding and functional bioassay experiments were performed to assess the expression in Chinese hamster ovary (CHO) cells and human prostate tissues. A confocal imaging study was subsequently performed.
Although Alexa-488-silodosin had roughly 10 times lower affinity for all α1-AR subtypes than silodosin, it had high selectivity for α1A-AR and α1L-AR in the binding and functional studies. The confocal imaging study demonstrated clear localization of the fluorescence on the membrane of CHO cells expressing α1A-AR but not α1B-AR and α1D-AR, and in the muscle layer of human prostate. While the fluorescent signal in the CHO cells disappeared in the presence of 3 nM prazosin, fluorescence in human prostate was observed even in the presence of 100 nM prazosin. The authors conclude that Alexa-488-silodosin is a powerful fluorescent probe with high selectivity for α1A-AR and α1L-AR. Thus, Alexa-488-silodosin successfully revealed the localization of the α1L-ARs in the muscle layer of human prostate without losing its distinct pharmacological profiles.
Role of TREK-1 Potassium Channel in Bladder Overactivity After Partial Bladder Outlet Obstruction
Animal models of partial bladder outlet obstruction (PBOO) have been used extensively to investigate neural and myogenic changes. Mouse models of PBOO show bladder hypertrophy, and increased detrusor cell excitability, micturition frequency and intravesical pressures, although the magnitude of these changes depends on the species and protocol. Changes in ion channel expression and/or function are likely important components of bladder smooth muscle cell excitability and bladder overactivity in long-term PBOO. Baker et al (page 793) from Reno, Nevada investigated whether mechanosensitive TREK-1 channels are present in the murine bladder and whether their expression is altered in PBOO, resulting in abnormal filling responses. They induced PBOO in CD-1 mice and allowed the mice to recover for 14 days. Cystometry was used to evaluate bladder pressure responses during filling at 25 μl per minute in obstructed animals and sham operated controls. TREK-1 channel expression was determined at the mRNA and protein levels by quantitative real-time polymerase chain reaction and Western blotting, respectively, and localization of the channel in the bladder wall was assessed by immunohistochemistry.
Obstructed bladders showed an approximately 2-fold increase in weight compared to those of sham operated animals. Expression of TREK-1 channel protein was significantly decreased in PBOO mice. Similarly immunohistochemistry showed a significant decrease in immunoreactivity of TREK-1 channels in detrusor smooth muscle in PBOO mice. L-methioninol, a blocker of TREK-1 channels, induced a significant increase in nonvoiding contractions during filling cystometry in sham operated mice but had no significant effect in PBOO mice, which exhibited an overactive detrusor phenotype. The authors suggest that the reduction of TREK-1 channels could be one of the factors contributing to bladder overactivity in the mouse model of PBOO. They conclude that TREK-1 channels participate in the stabilization of membrane potentials in the bladder detrusor during filling, and that down-regulation of these channels in detrusor myocytes is associated with bladder overactivity in PBOO.
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