Yves Deruyver

Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review.

Retrieval of spermatozoa is unfortunately still only successful in a subset of patients suffering from non‐obstructive azoospermia (NOA) by conventional testicular sperm extraction (TESE). Microdissection TESE may have some theoretical benefits over conventional TESE, but uncertainty exists about its superiority. The objective of this systematic review was therefore to compare the efficacy and safety of microTESE with conventional TESE in men with NOA. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis statement. Literature was searched for studies comparing outcome of conventional TESE with microdissection TESE. Primary outcome was sperm retrieval rate (SRR). Secondary outcomes were clinical predictors of sperm retrieval as well as complication rate. Of 62 articles, a total of seven studies were included in the final analysis. Overall SRR was significantly higher in the microTESE group in comparison with conventional TESE in five of these studies. Overall sperm retrieval ranged from 16.7 to 45% in the conventional TESE vs. 42.9 to 63% in the microTESE group. A sub‐analysis of the SRR according to testicular histology was available in four of the selected articles. MicroTESE in men with Sertoli cell only syndrome and hypospermatogenesis carried a small but significant more favourable outcome according to, respectively, two and one of the studies. Correlation of serum follicle stimulating hormone and testicular volume with positive outcome was variable. Fewer complications were observed on ultrasound examination after microTESE procedure. Clinical randomized studies comparing microTESE with conventional TESE in NOA are still lacking to date. Pseudo‐randomized prospective data, however, show more favourable sperm retrieval in NOA for microTESE, especially in histological patterns of patchy spermatogenesis such as Sertoli cell only syndrome. However, in patients with uniform histological patterns such as maturation arrest outcome of microTESE seems less favourable.

Essential Role of Transient Receptor Potential M8 (TRPM8) in a Model of Acute Cold-induced Urinary Urgency

BACKGROUND Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU. OBJECTIVE To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1. DESIGN, SETTING, AND PARTICIPANTS Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats. INTERVENTIONS An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test. RESULTS AND LIMITATIONS Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients. PATIENT SUMMARY Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans.

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead. TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria. TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on‐target, side‐effect. TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre‐clinical studies of LUT dysfunction and are awaiting clinical validation.

Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity

BACKGROUND Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling. OBJECTIVE To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity. DESIGN, SETTING, AND PARTICIPANTS Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate. RESULTS AND LIMITATIONS Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4-/-, rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4-/- mice was not apparent in the Trpv4-/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents. CONCLUSIONS Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling. PATIENT SUMMARY We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder.

(18F)FDG-PET brain imaging during the micturition cycle in rats detects regions involved in bladder afferent signalling

BackgroundThis feasibility study established an experimental protocol to evaluate brain activation patterns using fluorodeoxyglucose positron emission tomography ((18F)FDG-PET) during volume-induced voiding and isovolumetric bladder contractions in rats.MethodsFemale Sprague-Dawley rats were anaesthetized with urethane and underwent either volume-induced voiding cystometry or isovolumetric cystometry and simultaneous functional PET brain imaging after injection of (18F)FDG in the tail vein. Brain glucose metabolism in both groups was compared to their respective control conditions (empty bladder). Relative glucose metabolism images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping 12 (SPM12).ResultsDuring volume-induced voiding, glucose hypermetabolism was observed in the insular cortex while uptake was decreased in a cerebellar cluster and the dorsal midbrain. Relative glucose metabolism during isovolumetric bladder contractions increased in the insular and cingulate cortices and decreased in the cerebellum.ConclusionsOur findings demonstrate that volume-induced voiding as well as isovolumetric bladder contractions in rats provokes changes in brain metabolism, including activation of the insular and cingulate cortices, which is consistent with their role in the mapping of bladder afferent activity. These findings are in line with human studies. Our results provide a basis for further research into the brain control of the lower urinary tract in small laboratory animals.

MP26-10 NEUROGENIC DETRUSOR UNDERACTIVITY: SHOULD WE TARGET THE BLADDER?

alteration of histopathology and expression of TLR4 and NLRP3 inflammasome-related molecules in the bladder using spontaneously hypertensive rats (SHRs) as an OAB model. METHODS: Twenty-weeks-old male SHRs and Wistar Kyoto rats (control) were used. After voiding function was analyzed by using metabolic cages, the bladder was excised for analysis of histopathology and mRNA expression. Hematoxylin eosin and Masson0s trichrome stain were performed to analyze bladder inflammatory condition and fibrosis. Immunohistostaining for NLRP3, TLR4 was also performed. Expression levels of NLRP3, IL1b, IL-18, IL6, IL8 and TGFb mRNA in the bladder were investigated by real-time PCR. Statistical analysis was performed using Mann-Whitney U test. P value less than 0.05 was considered statistically significant. RESULTS: In voiding function analyses, single urine volume was significantly decreased and voiding frequency was significantly increased in SHRs compared to control rats. In histological evaluation, suburothelial fibrosis was shown in SHRs compared to controls. Furthermore, immunohistostaining showed localized expression of NLRP3 and TLR4 in the bladder urothelium in both groups. In RT-qPCR analyses, mRNA expression levels of NLRP3, TLR4, IL1b, IL-18, IL6, IL8 and TGFb were significantly increased in SHRs in the bladder compared to controls. CONCLUSIONS: These results suggest that activation of TLR4 associated with oxidative stress is implicated in bladder chronic inflammation, which leads to frequent urination through NLRP3 inflammasome pathways. Therefore, further clarification of interactions between TLR4 and inflammasome pathways may offer new therapeutic targets for OAB associated with chronic inflammation.

MP82-16 BLADDER SMOOTH MUSCLE CONTRACTILITY IS INHIBITED BY HC030031 INDEPENDENTLY OF TRPA1

INTRODUCTION AND OBJECTIVES: The exact etiology of LUTS in human is still poorly understood. Alpha1-blockers are widely used in the treatment of LUTS associated with BPH. Tamsulosin has been reported to possess a potential of increasing blood flow in bladder microcirculation. Using a characterized rat model of chronic pelvic ischemia, we have studied the ameliorating potential of tamsulosin on the changes in bladder function caused by chronic ischemia. METHODS: Chronic pelvic ischemia (CPI) was induced by causing bilateral endothelial injury of both iliac arteries and feeding a 2% cholesterol diet. A total of 60 male Sprague Dawley rats (18 weeks old) were divided into three groups: Control, CPI, and CPI-tamsulosin. The Control group received a regular diet and the CPI-tamsulosin group received tamsulosin (10 mg/kg/day) for 8 weeks. Eight weeks after surgery, half of the rats in the Control, CPI and CPI-tamsulosin groups were examined by cystometry and sacrificed for organ bath study. The other half of the rats from each group was examined 16 weeks after surgery (the CPI-tamsulosin group were continued treatment in the latter half of 8 weeks). RESULTS: The iliac arteries from the AI showed neo-intimal proliferation and vascular occlusion. This was not prevented by tamsulosin treatment. After 8 weeks, there was no difference between CPI and CPI-tamsulosin groups in micturition interval (MI), bladder capacity (Bcap), and voiding volume (VV). Those parameters in both groups were significantly less than in the Control group (P<0.05). After 16 weeks, those parameters were improved in CPI-tamsulosin group without changing other parameters. CONCLUSIONS: Tamsulosin treatment improved voiding function in rats with established chronic pelvic ischemia. The translational impact of this finding would be worth further study for improving the bladder function.

The use of imaging techniques in understanding lower urinary tract (dys)function

The ability to store urine in the bladder and to void at an appropriate time depends on several complex mechanisms in the lower urinary tract (LUT) and its neural control. Normal LUT function requires coordination of the urinary bladder, urethra, pelvic floor, efferent and afferent neurons and specific spinal cord and brain areas. These structures can be visualised using different imaging modalities, such as ultrasound, X-ray and magnetic resonance imaging. The supraspinal neural control of the LUT can be studied using functional brain imaging. During the last two decades, the many technological improvements of these imaging techniques have increased our knowledge of voiding dysfunction. Here, we review the different imaging modalities of the LUT and its neural control and discuss their importance for diagnosing and understanding voiding dysfunction.

797 Essential role of TRPM8 in a model of acute cold-induced urgency

Affiliations: KU Leuven, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Herestraat 49 box 802, 3000 Leuven KU Leuven, Laboratory of Experimental Urology, Department of Development and Regeneration, Herestraat 49 box 7003 41, 3000 Leuven TRP Research Platform Leuven (TRPLe) Co-first authors Corresponding author: KU Leuven Laboratory of Ion Channel Research Department of Cellular and Molecular Medicine Herestraat 49 bus 802 B-3000 Leuven, Belgium Tel.: +32-16-330217 E-mail: thomas.voets@med.kuleuven.be