Muscarinic receptor antagonists, the overactive bladder and efficacy against urinary urgency

The overactive bladder (OAB) is a debilitating condition in which patients suffer from urinary urgency, frequency and nocturiawith or without urge urinary incontinence. The mainstay of pharmacotherapy for OAB is muscarinic receptor antagonists, which havebeen shown to be effective treatments for the symptoms of OAB. The mechanism underlying the efficacy of antimuscarinic agentsagainst the symptoms of OAB is not completely understood. This review explores the role of bladder mucosal muscarinic receptors in the signaling pathways that are activated in response to bladder filling. The cholinergic system is seen to be involved in bladder afferent signaling at many levels and as such muscarinic receptor antagonists may affect bladder signaling via numerous pathways including release of mediators from the bladder urothelium and activation of suburothelial myofibroblasts and afferent nerves. Therefore the mucosal cholinergic system may represent another target for the antimuscarinic agents used to treat OAB

Nitric oxide, a survival factor for lens epithelial cells

Purpose: Nitric oxide (NO) is capable of promoting either cell death or cell survival depending on cell type and experimental conditions. In this study, the possible effects of NO on the viability of lens epithelial cells were investigated in an explant model used previously to identify cellular changes associated with posterior capsule opacification following cataract surgery. Methods: Rat lens epithelial explants prepared from weanling rats were cultured in a serum-free medium for five days with or without the addition of the nitric oxide synthase inhibitor, L-Nω-nitro-L-arginine methyl ester (L-NAME), using the inactive enantiomer D-NAME as a control. Alternatively, explants were cultured for nine days with or without the NO donor, sodium nitroprusside. Explants were assessed morphologically and immunohistochemically or by determining DNA content. Results: In the presence of L-NAME but not in controls, progressive rounding up and detachment of cells from the lens capsule occurred, leading to extensive cell loss. Affected cells showed apoptosis-like cell-surface blebbing and nuclear fragmentation. Conversely, inclusion of sodium nitroprusside suppressed the morphological changes and spontaneous cell loss that occurred when sparsely covered explants were cultured for nine days, increased cell coverage fourfold during that period, and prevented the expression of the transdifferentiation markers α-smooth muscle actin and fibronectin. In addition, whereas L-NAME exacerbated cell loss induced by culturing with 50 pg/ml transforming growth factor-β2, sodium nitroprusside offered protection. Conclusions: This study points to a previously unidentified role for NO as an endogenously produced survival factor for lens epithelial cells, raising the possibility of using NO deprivation as a means of removing residual lens cells following cataract surgery and thereby preventing posterior capsule opacification

Establishing consensus on nutrition competencies for medicine: a Delphi study

Background: Significant research, regulatory bodies and even governmental resolutions have identified meaningful nutrition education for medical and other healthcare professionals as a priority. Doctors are well placed to provide nutrition care, yet nutrition education in medicine remains inadequate regardless of country, setting, or year of training. There remains a need to establish an accepted benchmark on nutrition competencies for medicine, as without consensus standards there is little likelihood of uniform adoption. Objective: This study aimed to establish consensus on nutrition competencies using a Delphi process to inform a framework for nutrition education in medicine. Methods: A three-round modified online Delphi survey of experts in healthcare practice, education and training, and experts by experience (service users) was conducted to provide a comprehensive consensus on nutrition competencies for medical practice. Results: Fifty-two experts (15.1% response rate) participated in Round 1, 42 completed Round 2 and 47 completed Round 3. Participants included medical professionals, dietitians, academics working in health professions education and policymakers from Australia, New Zealand, the UK and Northern Ireland. Twenty-seven service users (57.5% response rate) completed the Round 1 questionnaire, 19 completed Round 2 and 16 completed Round 3. By consensus, 25 nutrition competencies for medicine were defined. The service user panel identified an additional seven skills and attributes considered important in the receipt of nutrition care. Competencies that achieved consensus broadly fell into themes of team-based care, communication, professionalism (eg, attributes) and health promotion and disease prevention. This informs broad skills that may be taught in a nutrition context but could be included in other domains. Conclusions: The findings suggest doctors need the knowledge and skills to consider the findings from nutrition screening and assessment, coordinate nutrition care when an individual may benefit from further assessment or intervention and provide support for advice delivered by other experts as part of a multidisciplinary approach

Effective Treatments of UTI—Is Intravesical Therapy the Future?

Urinary tract infection (UTI) afflicts millions of patients globally each year. While the majority of UTIs are successfully treated with orally administered antibiotics, the impact of oral antibiotics on the host microbiota is under close research scrutiny and the potential for dysbiosis is a cause for concern. Optimal treatment of UTI relies upon the selection of an agent which displays appropriate pharmacokinetic-pharmacodynamic (PK-PD) properties that will deliver appropriately high concentrations in the urinary tract after oral administration. Alternatively, high local concentrations of antibiotic at the urothelial surface can be achieved by direct instillation into the urinary tract. For antibiotics with the appropriate physicochemical properties, this can be of critical importance in cases for which an intracellular urothelial bacterial reservoir is suspected. In this review, we summarise the underpinning biopharmaceutical barriers to effective treatment of UTI and provide an overview of the evidence for the deployment of the intravesical administration route for antibiotics

Natural products for the treatment of urinary incontinence

This review summarises the material covered during a workshop entitled “Natural Products as Treatments for Urinary Incontinence” that was presented at the online ICS (Melbourne) annual conference held in 2021. The clinical and scientific evidence of the effectiveness of naturally sourced treatments such as traditional Chinese medicines, phytoestrogens and saw palmetto for lower urinary tract symptoms are discussed, and also the use of cranberry and D-mannose for the treatment of bacterial infections of the urinary tract. The workshop and this review finish with a look towards the future and a discussion of potential treatments to repair the barrier function of the urothelium, an action that may be useful in conditions such as interstitial cystitis/bladder pain syndrome

Porcine Bladder Urothelial, Myofibroblast, and Detrusor Muscle Cells: Characterization and ATP Release

ATP is released from the bladder mucosa in response to stretch, but the cell types responsible are unclear. Our aim was to isolate and characterize individual populations of urothelial, myofibroblast, and detrusor muscle cells in culture, and to examine agonist-stimulated ATP release. Using female pig bladders, urothelial cells were isolated from bladder mucosa following trypsin-digestion of the luminal surface. The underlying myofibroblast layer was dissected, minced, digested, and cultured until confluent (10–14 days). A similar protocol was used for muscle cells. Cultures were used for immunocytochemical staining and/or ATP release investigations. In urothelial cultures, immunoreactivity was present for the cytokeratin marker AE1/AE3 but not the contractile protein α-smooth muscle actin (α-SMA) or the cytoskeletal filament vimentin. Neither myofibroblast nor muscle cell cultures stained for AE1/AE3. Myofibroblast cultures partially stained for α-SMA, whereas muscle cultures were 100% stained. Both myofibroblast and muscle stained for vimentin, however, they were morphologically distinct. Ultrastructural studies verified that the suburothelial layer of pig bladder contained abundant myofibroblasts, characterized by high densities of rough endoplasmic reticulum. Baseline ATP release was higher in urothelial and myofibroblast cultures, compared with muscle. ATP release was significantly stimulated by stretch in all three cell populations. Only urothelial cells released ATP in response to acid, and only muscle cells were stimulated by capsaicin. Tachykinins had no effect on ATP release. In conclusion, we have established a method for culture of three cell populations from porcine bladder, a well-known human bladder model, and shown that these are distinct morphologically, immunologically, and pharmacologically

Nutrition competencies for medicine: an integrative review and critical synthesis.

OBJECTIVE: Globally, 11 million deaths are attributable to suboptimal diet annually, and nutrition care has been shown to improve health outcomes. While medically trained clinicians are well-placed to provide nutrition care, medical education remains insufficient to support clinicians to deliver nutrition advice as part of routine clinical practice. Competency standards provide a framework for workforce development and a vehicle for aligning health priorities with the values of a profession. Although, there remains an urgent need to establish consensus on nutrition competencies for medicine. The aim of this review is to provide a critical synthesis of published nutrition competencies for medicine internationally. DESIGN: Integrative review. DATA SOURCES: CINAHL, Medline, Embase, Scopus, Web of Science and Global Health were searched through April 2020. ELIGIBILITY CRITERIA: We included published Nutrition Competency Frameworks. This search was complemented by handsearching reference lists of literature deemed relevant. DATA EXTRACTION AND SYNTHESIS: Data were extracted into summary tables and this matrix was then used to identify common themes and to compare and analyse the literature. Miller's pyramid, the Knowledge to Action Cycle and the Dreyfus model of skill acquisition were also used to consider the results of this review. RESULTS: Using a predetermined search strategy, 11 articles were identified. Five common themes were identified and include (1) clinical practice, (2) health promotion and disease prevention, (3) communication, (4) working as a team and (5) professional practice. This review also identified 25 nutrition competencies for medicine, the majority of which were knowledge-based. CONCLUSIONS: This review recommends vertical integration of nutrition competencies into existing medical education based on key, cross-cutting themes and increased opportunities to engage in relevant, skill-based nutrition training

Immunocytochemical characterisation of cultures of human bladder mucosal cells

<p>Abstract</p> <p>Background</p> <p>The functional role of the bladder urothelium has been the focus of much recent research. The bladder mucosa contains two significant cell types: urothelial cells that line the bladder lumen and suburothelial interstitial cells or myofibroblasts. The aims of this study were to culture these cell populations from human bladder biopsies and to perform immunocytochemical characterisation.</p> <p>Methods</p> <p>Primary cell cultures were established from human bladder biopsies (n = 10). Individual populations of urothelial and myofibroblast-like cells were isolated using magnetic activated cell separation (MACS). Cells were slow growing, needing 3 to 5 weeks to attain confluence.</p> <p>Results</p> <p>Cytokeratin 20 positive cells (umbrella cells) were isolated at primary culture and also from patients' bladder washings but these did not proliferate. In primary culture, proliferating cells demonstrated positive immunocytochemical staining to cytokeratin markers (AE1/AE3 and A0575) as well fibroblasts (5B5) and smooth muscle (αSMA) markers. An unexpected finding was that populations of presumptive urothelial and myofibroblast-like cells, isolated using the MACS beads, stained for similar markers. In contrast, staining for cytokeratins and fibroblast or smooth muscle markers was not co-localised in full thickness bladder sections.</p> <p>Conclusions</p> <p>Our results suggest that, in culture, bladder mucosal cells may undergo differentiation into a myoepithelial cell phenotype indicating that urothelial cells have the capacity to respond to environmental changes. This may be important pathologically but also suggests that studies of the physiological function of these cells in culture may not give a reliable indicator of human physiology.</p

Altered urothelial ATP signaling in a major subset of human overactive bladder patients with pyuria

Overactive Bladder (OAB) is an idiopathic condition, characterized by urgency, urinary frequency, and urgency incontinence, in the absence of routinely traceable urinary infection. We have described microscopic pyuria (?10 wbc/?l) in patients suffering from the worst symptoms. It is established that inflammation is associated with increased ATP release from epithelial cells, and extracellular ATP originating from the urothelium following increased hydrostatic pressure is a mediator of bladder sensation. Here, using bladder biopsy samples, we have investigated urothelial ATP signaling in OAB patients with microscopic pyuria. Basal, but not stretch-evoked, release of ATP was significantly greater from the urothelium of OAB patients with pyuria than from non-OAB patients or OAB patients without pyuria (<10 wbc/?l). Basal ATP release from the urothelium of OAB patients with pyuria was inhibited by the P2 receptor antagonist suramin and abolished by the hemichannel blocker carbenoxolone, which differed from stretch-activated ATP release. Altered P2 receptor expression was evident in the urothelium from pyuric OAB patients. Furthermore, intracellular bacteria were visualized in shed urothelial cells from ?80% of OAB patients with pyuria. These data suggest that increased ATP release from the urothelium, involving bacterial colonization, may play a role in the heightened symptoms associated with pyuric OAB patients