T. Bschleipfer

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

Significance We report the presence of a previously unidentified cholinergic, polymodal chemosensory cell in the mammalian urethra, the potential portal of entry for bacteria and harmful substances into the urogenital system. These cells exhibit structural markers of respiratory chemosensory cells (“brush cells”). They use the classical taste transduction cascade to detect potential hazardous compounds (bitter, umami, uropathogenic bacteria) and release acetylcholine in response. They lie next to sensory nerve fibers that carry acetylcholine receptors, and placing a bitter compound in the urethra enhances activity of the bladder detrusor muscle. Thus, monitoring of urethral content is linked to bladder control via a previously unrecognized cell type. Chemosensory cells in the mucosal surface of the respiratory tract (“brush cells”) use the canonical taste transduction cascade to detect potentially hazardous content and trigger local protective and aversive respiratory reflexes on stimulation. So far, the urogenital tract has been considered to lack this cell type. Here we report the presence of a previously unidentified cholinergic, polymodal chemosensory cell in the mammalian urethra, the potential portal of entry for bacteria and harmful substances into the urogenital system, but not in further centrally located parts of the urinary tract, such as the bladder, ureter, and renal pelvis. Urethral brush cells express bitter and umami taste receptors and downstream components of the taste transduction cascade; respond to stimulation with bitter (denatonium), umami (monosodium glutamate), and uropathogenic Escherichia coli; and release acetylcholine to communicate with other cells. They are approached by sensory nerve fibers expressing nicotinic acetylcholine receptors, and intraurethral application of denatonium reflexively increases activity of the bladder detrusor muscle in anesthetized rats. We propose a concept of urinary bladder control involving a previously unidentified cholinergic chemosensory cell monitoring the chemical composition of the urethral luminal microenvironment for potential hazardous content.

Diagnostic Value of Magnetic Resonance Imaging in Peyronie’s Disease—A Comparison Both with Palpation and Ultrasound in the Evaluation of Plaque Formation ☆

OBJECTIVE To compare the value of magnetic resonance imaging (MRI) with palpation and ultrasound in the evaluation of plaque formation in Peyronies disease. METHODS 57 patients underwent a standardized diagnostic procedure to evaluate plaque formation consisting of palpation and ultrasonography (7.5 MHz). MRI was performed during flaccidity and during erection induced by Prostaglandin E(1) including intravenous application of Gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). RESULTS With all methods, 93 plaques have been detected in 57 patients. 85 plaques (91.4%) have been evaluated by palpation alone. Using ultrasound, 52 of these 93 plaques (55.9%) were detectable. This is equivalent to 61.1% of the palpable plaques. MRI confirmed 58 of the palpated plaques (68.2%) and exposed 8 primarily not palpable plaques at the penile basis. MRI revealed more palpable plaques than ultrasound, but this finding was not significant (p = 0.083). By means of sonography, calcification was evident in 14 plaques. MRI failed in revealing any calcification. After application of Gd-DPTA, 5 of 57 patients (9%) demonstrated contrast enhancement indicating local inflammation. None of these patients reported on penile pain. CONCLUSIONS Penile palpation in combination with ultrasound represents the method of choice to diagnose plaque formation in Peyronies disease. MRI provides better information on plaque formation at the penile basis. Calcification can only be proven by ultrasound, not by MRI. There may be additional information by MRI about local inflammation. A prospective study comparing the histological and MRI findings should be performed to answer the question, if pain is really associated with inflammation.

Prostatitis and Male Pelvic Pain Syndrome

BACKGROUND The prostatitis syndrome is a multifactorial condition of largely unknown etiology. The new NIH classification divides the prostatitis syndrome into a number of subtypes: acute bacterial prostatitis, chronic bacterial prostatitis, inflammatory and noninflammatory chronic pelvic pain syndrome, and asymptomatic prostatitis. METHODS This article is based on a selective review of the literature regarding the assessment and management of the prostatitis syndrome and on a recently published consensus statement of the International Prostatitis Collaboration Network. RESULTS Pathogenic organisms can be cultured only in acute and chronic bacterial prostatitis. These conditions should be treated with antibiotics, usually fluoroquinolones, for an adequate period of time. 90% of patients with prostatitis syndrome, however, suffer not from bacterial prostatitis but from chronic (abacterial) prostatitis / chronic pelvic pain syndrome (CP/CPPS). It remains unclear whether CP/CPPS is of infectious origin, and therefore the utility of a trial of antimicrobial treatment is debatable. Treatment with alpha receptor blockers is recommended if functional subvesical obstruction is documented or suspected. Symptomatic therapy for pelvic pain should be given as well. CONCLUSIONS The prostatitis syndrome is a complex condition with a tendency toward chronification. It is important, therefore, that the patient be fully informed about the diagnostic uncertainties and the possibility that treatment may meet with less than complete success.

Acute epididymitis in ultrasound: Results of a prospective study with baseline and follow-up investigations in 134 patients

OBJECTIVES To perform a comprehensive follow-up analysis of ultrasonographic scrotal features and associated signs in patients with acute epididymitis. METHODS Between 2007 and 2012, 134 adults (median age 54 years) with acute epididymitis underwent scrotal ultrasonography and palpation at first presentation and after 2 weeks and 3 months. RESULTS At first presentation, 61 patients (45.5%) had hydrocele, 63 (47.0%) concomitant orchitis, and 8 (5.9%) epididymal abscess. Epididymitis was predominantly located in 24 cases (17.9%) in the head, 52 cases (38.8%) in the tail, and 58 cases (43.3%) in both. On the affected side, testicular volume was 16.9 ± 6.8 ml and peak systolic velocity of the testicular artery was 23.7 ± 7.5 cm/s, compared to the healthy side with 12.3 ± 4.4 ml and 9.5 ± 3.6 cm/s respectively (P<0.001). Concomitant orchitis was associated with hydrocele, testicular enlargement and pain (P<0.01). Orchiectomy due to secondary testicular infarction was necessary in four cases, while in all other patients ultrasound parameters normalized. Only 16/90 patients (17.8%) showed a persistent epididymal swelling after 3 months. CONCLUSIONS Common ultrasound features include hydrocele, epididymal enlargement, hyperperfusion, and testicular involvement. Under conservative treatment, ultrasound parameters normalize without evidence of testicular atrophy even in patients with epididymal abscess or concomitant orchitis.

Long-Term Results of Plaque Thinning with Carbide Burs, Small Incisions and Venous Grafting for Correcting Complex Penile Curvature in Peyronie’s Disease: Poor Results of an “Ideal” Approach

PURPOSE We evaluated the long-term results of plaque thinning by carbide burs, small transverse incisions and venous grafting for correcting complex penile curvature in patients with Peyronies disease. MATERIALS AND METHODS A total of 13 patients with Peyronies disease and complex penile curvature received plaque thinning by carbide burs equipped with a fraise, small plaque incision and venous grafting. All patients were available for long-term followup at a mean of 29 months. Preoperatively the mean dorsal curvature angle was 73 degrees with an additional malrotation in 4 patients. Followup consisted of a standardized interview and 3-dimensional photo documentation during erection. RESULTS Although penile straightening was achieved intraoperatively, dorsal curvature (mean 35 degrees) recurred in 8 men, of whom 3 noticed this deterioration after a longer period. Penile shortening (mean 3.3 cm.) occurred in 7 patients, and decreased rigidity during intercourse occurred in 4. CONCLUSIONS Hypothetically, a combined technique of thinning, incision and grafting seems to be an ideal surgical approach for correction of complex penile curvatures in Peyronies disease without plaque excision. Although the penis had been completely straightened intraoperatively, severe dorsal curvatures recurred and significant penile shortening became obvious in more than half of the patients. Manipulation of the plaque may be associated with activation of the disease, with all of the risks of recurrence and deterioration. Due to the poor results of the thinning procedures, we stopped using this surgical approach and now prefer a combination of small incisions and grafting only.

Systemic Atherosclerosis Causes Detrusor Overactivity: Functional and Morphological Changes in Hyperlipoproteinemic apoE–/–LDLR–/– Mice

PURPOSE The prevalence of systemic atherosclerosis and overactive bladder/detrusor overactivity increases almost simultaneously with age but an association between these diseases has not yet been proved. We evaluated changes in bladder function and morphology, including vascularization, in apoE(-/-)LDLR(-/-) double knockout mice with systemic atherosclerosis but without central nervous system involvement. MATERIALS AND METHODS Cystometry was performed in awake, freely moving 60-week-old apoE(-/-)LDLR(-/-) mice and C57BL/6N controls. The mice were sacrificed and perfused with Microfil® contrast medium. The bladder was excised, dissected and scanned by nano-computerized tomography, including 3-dimensional reconstruction. Samples then underwent histomorphological analysis. RESULTS In apoE(-/-)LDLR(-/-) mice cystometry revealed a significant decrease in the peak-peak interval, micturition interval, functional bladder capacity and micturition volume. However, maximum bladder pressure increased. Nano-computerized tomography revealed a significant reduction in bladder wall thickness, segment volume, vascular volume and the vascular volume fraction. Histomorphologically bladder specimens showed a thickened media of intramural vessels, activated endothelial cells and intramural inflammatory cells. CONCLUSIONS To our knowledge this study presents a new in vivo mouse model of nonneurogenic detrusor overactivity caused by systemic atherosclerosis. Decreased bladder wall vascularization seems to be a major factor for detrusor overactivity onset. Capillaries are rarified with reduced lumina due to thickened media. Activated endothelial cells and the infiltration of inflammatory cells in apoE(-/-)LDLR(-/-) mice underlines once more that atherosclerosis is an inflammatory process that may also be relevant to the onset of detrusor overactivity.

Pollen extract for chronic prostatitis-chronic pelvic pain syndrome.

Prostatitis syndrome is a frequent condition in men. It is not known in most patients if the prostate is the only organ involved. Therefore, the disease is characterized as chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS). Although many studies have been performed in patients with CP-CPPS, current trial evidence is conflicting and therapeutic options are controversial. Given the need for long-term treatment in CP-CPPS patients, phytotherapeutics, such as pollen extract, are an option due to few side effects. Preclinical studies on pollen extract have shown effects on smooth muscles of the bladder and urethra, strong antiinflammatory effects, and antiproliferative effects.

Bladder outlet obstruction influences mRNA expression of cholinergic receptors on sensory neurons in mice.

AIMS In patients with bladder outlet obstruction (BOO), dysregulation of bladder afferent neurons seems to contribute to irritative symptoms. Cholinergic receptors, addressed by both neuronal and non-neuronal (urothelial) acetylcholine, can alter neuronal excitability. Thus we investigated the influence of BOO on the expression of muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors in the lumbosacral dorsal root ganglia (DRG) of mice. MAIN METHODS BOO was induced in 13 C57/BL6 mice by partial suturing of the urethra. Eleven mice were sham-operated (loose/freely movable suture around the urethra), and eleven untreated mice served as controls. Cystometry was performed five weeks later in conscious mice. DRG at segmental levels L5-S2 were dissected and real-time quantitative PCR was performed. Expression of mAChR subtypes M1-M5 and nAChR subunits α2-7, α9-10, β2-4 was examined. KEY FINDINGS Expression of all mAChR subtypes and nAChR subunits α3-7, α10, β2-4 was detected. Expression of α2 and α9 was absent. Rank order of expression was M2>M4>M3>M5>M1, α3≥α6>α7>α4>α10>α5 and β2>β4>β3 in untreated animals. BOO mice presented distinct obstruction with development of residual urine. Sham mice showed only minimal BOO. Relative mRNA expression of nAChR subunits revealed significant reduction of α3, α5, α6, α10 and β4 in sham-operated vs. untreated mice. In BOO vs. sham-operated mice, reduction of nAChR subunits α10 (p=0.038) and α5 (p=0.053) was found. SIGNIFICANCE BOO has a considerable impact on nAChR, but not on mAChR mRNA expression in sensory neurons. We hypothesize that a reduction in mRNA expression of nAChR subunits represents a link to altered sensitivity under non-obstructive conditions.

Does bladder outlet obstruction alter the non-neuronal cholinergic system of the human urothelium?

AIMS Alterations of the bladder sensory system are considered to contribute to detrusor overactivity (DO) when patients suffer from bladder outlet obstruction (BOO). The urothelium is one part of this sensory system and it harbors a non-neuronal cholinergic system (NNCS). We aimed to investigate if BOO causes alterations in the NNCS. MAIN METHODS Urothelial specimens were collected by endoscopy from six male controls and eight male patients suffering from BOO and DO. The samples were examined by immunofluorescence (IF) and real-time RT-PCR for high-affinity choline transporter-1 (CHT1), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), organic cation transporters OCT1-3, muscarinic receptor (mAChR) subtypes M1-M5 and nicotinic receptor (nAChR) subunits α7, α9 and α10. KEY FINDINGS ChAT, VAChT and OCT2 are not present in the male urothelium. Real-time RT-PCR and IF detected all other investigated targets. Rank order of expression was M2≫M3=M5>M4=M1 for mAChR subtypes and α7≫α10>α9 for nAChR subunits. Statistical analysis of RT-PCR results did not detect significant differences between patients and controls. Only IF detected differences between both groups: α9-Immunolabeling was increased in all BOO/DO patients. SIGNIFICANCE BOO does not induce considerable alterations of the human urothelial NNCS on mRNA level. Expression of mAChRs, CHT1, OCT1 and OCT3 is not significantly affected by BOO. Thus, transport mechanisms for choline and acetylcholine (ACh) stay unaltered. BOO increases immunolabeling of α9-nAChR but whether this sole finding contributes to the onset of DO seems questionable. Comparing the present results with our previous work, the urothelial NNCS does not differ between men and women.

Cholinergic urethral brush cells are widespread throughout placental mammals

We previously identified a population of cholinergic epithelial cells in murine, human and rat urethrae that exhibits a structural marker of brush cells (villin) and expresses components of the canonical taste transduction signaling cascade (α-gustducin, phospholipase Cβ2 (PLCβ2), transient receptor potential cation channel melanostatin 5 (TRPM5)). These cells serve as sentinels, monitoring the chemical composition of the luminal content for potentially hazardous compounds such as bacteria, and initiate protective reflexes counteracting further ingression. In order to elucidate cross-species conservation of the urethral chemosensory pathway we investigated the occurrence and molecular make-up of urethral brush cells in placental mammals. We screened 11 additional species, at least one in each of the five mammalian taxonomic units primates, carnivora, perissodactyla, artiodactyla and rodentia, for immunohistochemical labeling of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), villin, and taste cascade components (α-gustducin, PLCβ2, TRPM5). Corresponding to findings in previously investigated species, urethral epithelial cells with brush cell shape were immunolabeled in all 11 mammals. In 8 species, immunoreactivities against all marker proteins and ChAT were observed, and double-labeling immunofluorescence confirmed the cholinergic nature of villin-positive and chemosensory (TRPM5-positive) cells. In cat and horse, these cells were not labeled by the ChAT antiserum used in this study, and unspecific reactions of the secondary antiserum precluded conclusions about ChAT-expression in the bovine epithelium. These data indicate that urethral brush cells are widespread throughout the mammalian kingdom and evolved not later than about 64.5millionyears ago.