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Aims To present a synopsis of the presentations and discussions from Think Tank I, “Implications for afferent–urothelial bidirectional communication” of the 2014 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK.

Introduction Neural stimulation has become an established minimally invasive treatment for various lower urinary tract symptoms. The results both short- and long-term are encouraging, however, there is still a lack of knowledge of obvious risk factors, which may affect the outcome of treatment. Although neural stimulation has been embraced by healthcare professionals and patients, the exact mechanism by which neural stimulation works is still unclear. Discussion A condense review of knowledge available on this topic is presented. Several research questions are raised. Outlines of research studies, both clinical and basic science, are suggested. Conclusions Further studies are necessary to understand mechanism of action of neural stimulation and its implications on treatment outcomes. Neurourol. Urodynam. 33:618–621, 2014. © 2014 Wiley Periodicals, Inc.

Aims To present a brief review on discussions from “Do we understand any more about lower urinary tract interstitial cells?” session at the 2013 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. Methods Discussion focused on bladder interstitial cell (IC) subtypes, their localization and characterization, and communication between themselves, the urothelium, and detrusor smooth muscle. The role of ICs in bladder pathologies and new methods for studying ICs were also addressed. Results ICs have been studied extensively in the lower urinary tract and have been characterized based on comparisons with ICs of Cajal in the gastro-intestinal tract. In fetal bladders it is believed that ICs drive intrinsic contractions to expel urine through the urachus. These contractions diminish postpartum as bladder innervation develops. Voiding in human neonates occurs when filling triggers a spinal cord reflex that contracts the detrusor; in rodents, maternal stimulation of the perineum triggers voiding. Following spinal cord injury, intrinsic contractions, and spinal micturition reflexes develop, similar to those seen during neonatal development. These enhanced contractions may stimulate nociceptive and mechanosensitive afferents contributing to neurogenic detrusor overactivity and incontinence. The IC-mediated activity is believed to be initiated in the lamina propria by responding to urothelial factors. These IC may act syncytially through gap junction coupling and modulate detrusor activity through unknown mechanisms. Conclusion There has been a great deal of information discovered regarding bladder ICs, however, many of their (patho)physiological functions and mechanisms are still unclear and necessitates further research. Neurourol. Urodynam. 33:573–576, 2014. © 2014 Wiley Periodicals, Inc.

Background Botulinum neurotoxins type A (BoNT/A), β3-adrenergic receptor agonists, and phosphodiesterase type 5 (PDE5) inhibitors are promising agents that mitigate lower urinary tract symptoms by attenuating the sensory system. However, whether they act directly on afferent nerves or indirectly through the other cell types is unclear. Methods Spinal cord transected female mice were used as a model for neurogenic bladder overactivity. In vivo methods utilized decerebrate mouse cystometry. In vitro approaches included optical mapping of Ca2+ transient, single unit afferent nerve recordings and tension measurements from bladder sheets and wall cross-sections. Immunohistochemistry was used to measure the expression of β3-adrenergic receptors on dorsal root ganglion (DRG) neurons. Results Our unique approaches revealed the direct effects of BoNT/A in inhibiting neuropeptide release and firing rates in afferents following bladder injections. β3-adrenergic receptor agonists are demonstrated to directly inhibit afferent nerve firing independent of the relaxing effects on bladder smooth muscle. Moreover, data suggest the expression of these receptors on DRG neurons that send projections to the bladder. The mechanism of action of PDE5 inhibitors on bladder overactivity is discussed. Discussion The questions raised during the plenary session of the 2011 International Consultation on Incontinence-Research Society meeting regarding the benefits of BoNT/A, β3-adrenergic receptor agonist and PDE5 inhibitor treatments of overactive bladder are addressed. Conclusion Our findings suggest that the abovementioned agents, in low enough concentrations, can directly inhibit afferent excitability without decreasing detrusor contractility. Accordingly, they have considerable potential for treating the sensory component of lower urinary tract dysfunctions. Neurourol. Urodynam. 31:300–308, 2012. © 2012 Wiley Periodicals, Inc.

Common methods for inducing neurogenic bladder overactivity include: (1) spinal cord transection or contusion injury, (2) supraspinal injury (decerebration, local lesions, middle cerebral artery occlusion and (3) systemic (e.g., cyclophosphamide) or intravesical administration of irritant or inflammatory agents (e.g., acrolein, acid, lipopolysaccharide). These insults can cause peripheral, spinal and supraspinal effects which are difficult to resolve using traditional cystometry alone. To address this problem, we have developed new methods as well as new highly reproducible models to study neurogenic bladder dysfunction in the mouse. These models include direct sensitization of the bladder using ionizing radiation or indirect sensitization through colonic irradiation (figure 1). The classic model for neurogenic bladder overactivity is spinal cord injury which results in non-voiding contractions during the filling phase. However, there is also an intrinsic myogenic component that is present when studied in vitro. Our radiation models are purely neurogenic and do exhibit overactivity in isolated tissues. Figure: 1 New in vitro studies utilize bladder-urethra sheets, spinal cord slices and in-line cultured cells. Bladder-urethra sheets can be isolated with the hypogastric (T11-L2) and pelvic (L6-S2) nerves and imaged for the propagation of optical activity along the bladder wall simultaneously with afferent nerve and tension recordings. Alternatively, bladder sheets can be mounted vertically as cross-sections for measuring the spread of activity across the wall from mucosa to serosa. Spinal cord slices are sectioned 0.5 to 1 mm thick to include the dorsal and ventral roots which can be stimulated to optically map pathologically-induced changes in spinal cord circuitry. In-line cultured cells, on the other hand, allow for different linear arrangements of urothelial, interstitial, smooth muscle and dorsal root ganglion cells to map alterations in the flow of information in cell-to-cell communication. In vivo studies utilize cystometry which can be combined with cerebro-cortical imaging of optical activity during bladder filling and emptying. The new models of neurogenic overactivity are induced by irradiation of the bladder (direct sensitization) or colon (indirect cross-sensitization) both of which result in inflammation and urothelial damage leading to bladder overactivity. The changes induced by these models have been compared to those induced by the well established models of chronic spinal cord transection at the thoracic (T8-T9) and lumbar (L4-L5) levels.

A substantial portion of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated, enhanced and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source for drug targets. Established drug therapies such as muscarinic receptor antagonists, and two emerging therapies, beta(3)-adrenergic receptor agonists and botulinum toxin type-A, may act partly through afferent mechanisms. This review focuses on these two new principles and new and established methods for determining their sites of action. It also provides brief information on the innervation of the bladder, afferent receptors and transmitters and how these may communicate with the urothelium, interstitial cells and detrusor smooth muscle to regulate micturition. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms and urgency sensations are also covered. This work is the result from 'Think Tank' presentations, and the lengthy discussions that followed, at the 2010 International Consultation on Incontinence Research Society meeting in Bristol, UK. Neurourol. Urodynam. 30:684-691, 2011.

OBJECTIVE: To assess the safety and efficacy of anticholinergics in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) by a systematic review of published reports and a meta-analysis of the reported outcomes. METHODS: We searched Medline, Embase and Cochrane databases (1966-2006), and hand-searched relevant reference lists and conference proceedings, for studies on the use of anticholinergics in men with BPH or bladder outlet obstruction. Eligible studies were assessed for quality and foreign language studies were translated. We collected data on all reported outcomes, conducted meta- analyses on the maximum urinary flow rate (Q(max)), postvoid residual urine volume (PVR) and volume at first contraction, and calculated the acute urinary retention (AUR) rate. We used sensitivity analysis to confirm the findings. RESULTS: We identified five randomized controlled trials (RCTs) and 15 observational studies. Four RCTs incorporating 633 patients were included in the meta-analyses. Anticholinergics did not significantly alter Q(max) (0.1 mL/s, 95% confidence interval, CI, 0.6-0.7). The PVR was increased by 11.6 mL (95% CI 4.5-18.6) although there was no significant difference between AUR rates. The total International Prostate Symptom Scores (IPSS) were not significantly different, but there were improvements for IPSS storage subscores in one RCT. The AUR rate was 0.3% at the 12-week follow-up in 365 men in the RCTs and observational studies. CONCLUSION: Anticholinergic use in men with LUTS suggestive of BPH appears to be safe. Further studies are required to establish efficacy with a suitable precision.

The addition of 1-chloroalkyl p-tolyl sulfoxides to carbonyl compounds gave adducts which were then converted to chlorooxiranes in two steps with good overall yields. The treatment of the chlorooxiranes with various nucleophiles gave α-hygroxy α′-substituted ketones or α-hydroxy ketones in good yields.

A 34-year-old female visited our hospital because of epigastralgia. We performed an upper gastrointestinal x-ray examination, and both conventional endoscopy and dye-spraying endoscopy (indigo-carmine contrast method). We diagnosed early gastric lymphoma which simulated Borrmann 3 type gastric cancer with IIb type early gastric cancer on the middle body and reactive lymphoreticular hyperplasia (RLH) of cobble stone-like granular pattern by endoscopic appearance on the lower body. Although dye-spraying endoscopy showed the details of the mucosa, it was very difficult to diagnose the lesions correctly by gross appearance alone. Because gastric lymphoma arises from the mucosal or submucosal layer and spreads in the mucosa diffusely, ultrasonic visualization by echo-endoscopy might be useful in the diagnostic procedure. We report a case of early gastric lymphoma coexisting with RLH; both lesions showed uncommon endoscopic features.