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Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic lower urinary tract condition. Patients with IC/BPS suffer from debilitating pain and urinary urgency. The underlying etiology of IC/BPS is unknown and as such current treatments are mostly symptomatic with no real cure. Many theories have been proposed to describe the etiology of IC/BPS, but this review focuses on the role of inflammation. In IC/BPS patients, the permeability of the urothelium barrier is compromised and inflammatory cells infiltrate the bladder wall. There are increased levels of many inflammatory mediators in patients with IC/BPS and symptoms such as pain and urgency that have been associated with the degree of inflammation. Recent evidence has highlighted the role of purinergic receptors, specifically the P2X7 receptor, in the process of inflammation. The results from studies in animals including cyclophosphamide-induced hemorrhagic cystitis strongly support the role of P2X7 receptors in inflammation. Furthermore, the deletion of the P2X7 receptor or antagonism of this receptor significantly reduces inflammatory mediator release from the bladder and improves symptoms. Research results from IC/BPS patients and animal models of IC/BPS strongly support the crucial role of inflammation in the pathophysiology of this painful disease. Purinergic signaling and purinergic receptors, especially the P2X7 receptor, play an undisputed role in inflammation. Purinergic receptor antagonists show positive results in treating different symptoms of IC/BPS.

Aim: Dietary modification is integral to the management of end stage kidney disease. However, adherence to the renal diet is poor. Few studies have explored the perspectives of renal dietitians and how they work with patients to facilitate dietary change. The objectives of this study were to explore the experiences of renal dietitians about educating patients with end stage kidney disease; and to describe the strategies perceived to help patients understand the renal diet. Methods: Semi-structured interviews based on Sensemaking theory were conducted with renal dietitians (n=27) working in Australia and New Zealand from a range of metropolitan, regional and remote areas. Results: Five major themes across two categories were derived from the data. The renal dietitians in this study experienced feelings of frustration, frequently worked in practice environments with limited or inadequate resources and perceived that establishing trust and demonstrating empathy were important to sense making. Renal dietitians helped patients make sense of and understand the diet by clarifying ambiguities and conflicting information; and simplifying complexity by using simple explanations, individualised advice and practical support. These strategies were considered critical to the renal diet sense making process. Conclusions: The experience of providing renal diet advice to adults with end stage kidney disease was emotionally and professionally challenging. Alternative approaches to patient education may help dietitians to empower patients to better understand the renal diet. Further research exploring the experiences of learning about the renal diet from the patient and carer perspective would also help to inform future alternative approaches.

A prominent role of ATP in bladder sensation via the activation of purinergic receptors on sensoryafferent neurons to regulate urinary bladder functions under normal and pathophysiological conditionshas been established. Extracellular ATP signalling is altered substantially in bladder diseases, such asoveractive bladder and interstitial cystitis. However, cellular pathways responsible for ATP release fromthe bladder remain largely unknown. Thus, the present thesis aimed to investigate the role of pannexin-1,CALHM1, connexin (Cx) 43 and Cx45 hemichannels in mediating ATP release in the urinary bladder.The expression and localisation of pannexin-1, CALHM1, Cx43 and Cx45 were studied in the porcinebladder, as well as in human urothelial RT4 cells. Double labelling with cell marker antibodies confirmedthe expression and localisation of pannexin-1, CALHM1, Cx43 and Cx45 in urothelial, suburothelial anddetrusor muscle cells of the porcine bladder, as well as in human urothelial RT4 cells. Inhibition ofpannexin-1, CALHM1, Cx43 and Cx45 channels in the presence of their respective inhibitorssignificantly reduced ATP release from porcine urothelial cells and from human urothelial RT4 cells inresponse to hypotonic induced stretch. Extracellular Ca2+ depletion induced ATP release was alsosignificantly attenuated by the blockage of the CALHM1, Cx43 and Cx45 channels.Moreover, to study the barrier functions of urothelium, an in vitro model of inflammation was developedin primary cultures of porcine urothelial cells. In this model, TNFα and IL-1β caused a tight junctiondisruption in urothelial cells, as demonstrated by reduced transepithelial electrical resistance andfragmentation or absence of tight junction protein ZO-1. TNFα and IL-1β induced urothelial barrierdamage was prevented by incubation of urothelial cells with the pannexin-1 channel blocker, 10Panx1.This is the first study to show that pannexin-1, CALHM1, Cx43 and Cx45 are functionally expressed inthe porcine bladder

Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.

Background: Dietary modification is an integral part of chronic kidney disease (CKD) management. However, adherence to the renal diet is often suboptimal. Methods: The aims of this study were to (i) describe the experiences of patients with CKD and their carers in their process of interpreting and implementing renal dietary advice; (ii) to explore strategies they used to make sense of and apply renal diet information and (iii) to develop recommendations for improved clinical practice. To achieve these aims, individual semi-structured interviews with 26 patients and 10 carers were conducted, using interview questions guided by Sensemaking theory. Findings: Six themes emerged from the data which did not differ according to CKD stage, geographic location or renal replacement therapy (RRT) type. The renal diet was perceived by patients and carers to be overwhelming, frustrating and emotionally demanding; as well as being complex and challenging. To help make sense of and apply renal dietary advice, participants highly valued the input of the dietitian; and patients believed that their carer support was important. Individual problem-solving strategies were developed by participants to help them make sense of the renal diet, and many of them expressed a desire for additional resources and/or support. Conclusions: This study highlights that learning to make sense of renal diet information is an emotionally challenging journey for patients and carers. In addition to utilising the expertise of dietitians, carer support was perceived to be integral to learning and using renal dietary advice. The study describes a number of important problem-solving strategies utilised by patients and carers, as well as recommendations to help improve sensemaking and adherence to the renal diet.

Aim: The aim of this study was to compare the extent of cognitive impairment and the types of cognitive deficits in an Australian cohort of four patient groups with end stage kidney disease. Characteristics predicting the presence of cognitive impairment were also evaluated. Methods: Observational cross sectional study of one hundred and fifty five patients with end stage kidney disease recruited from a regional Australian renal unit. Eligible participants included those whose estimated Glomerular Filtration Rate was < 30 ml/min per 1.73m2; were undertaking peritoneal or hemodialysis, or had received a kidney transplant. The Montreal Cognitive Assessment tool was used to screen the study participants for cognitive impairment and evaluate cognitive deficits. Cognitive impairment was defined as a total Montreal Cognitive Assessment tool score ≤24/30. Results: The extent of cognitive impairment varied between the four groups with end stage kidney disease. Factors predicting the presence of cognitive impairment included undertaking dialysis, age ≥65, male gender, and the presence of diabetes or cerebrovascular disease. Deficits in executive function, attention, language, visuospatial skills, memory and orientation were common amongst the study participants, and these deficits varied according to which end stage kidney disease group the participants were in. Limitations to the study included the cross sectional design and that the presence of confounders like depression were not recorded. Conclusion: The impact of disparities in the cognitive capabilities identified in this study are likely to be far reaching. Tailoring of education and self management programs to the cognitive deficits of individuals is required.

Psoriasis is a chronic inflammatory skin disorder, characterised by epidermal hyperplasia (acanthosis) and leukocyte infiltration of the skin. Current therapies are inadequate, highlighting the need for new therapeutic targets. The P2X7 receptor is implicated in the pathogenesis of psoriasis. This study investigated the role of P2X7 in imiquimod (IMQ)-induced psoriasis-like inflammation. Topically applied IMQ caused twofold greater ear swelling in BALB/c mice compared to C57BL/6 mice, which encode a partial loss-of-function missense mutation in the P2RX7 gene. However, there was no difference in histological skin pathology (acanthosis and leukocyte infiltration) between the two strains. IMQ treatment up-regulated P2X7 expression in skin from both mouse strains. Additionally, IMQ induced ATP release from cultured human keratinocytes, a process independent of cell death. Injection of the P2X7 antagonist Brilliant Blue G (BBG) but not A-804598 partly reduced ear swelling compared to vehicle-injected control mice. Neither antagonist altered skin pathology. Moreover, no difference in ear swelling or skin pathology was observed between C57BL/6 and P2X7 knock-out (KO) mice. Flow cytometric analysis of IMQ-treated skin from C57BL/6 and P2X7 KO mice demonstrated similar leukocyte infiltration, including neutrophils, macrophages and T cells. In conclusion, this study demonstrates that P2X7 is not essential for development of IMQ-induced psoriasis-like inflammation but does not exclude a role for this receptor in psoriasis development in humans or other mouse models of this disease.

Evidence-based medical practice is best achieved by developing research understanding in medical practitioners. To this end, medical councils worldwide increasingly recognise the importance of medical schools graduating students with well-developed research skills and research capacity. To meet this need, the principles of programmatic assessment were implemented in designing a research and critical analysis curriculum and assessment program that aimed to enhance the research and critical analysis skills of medical students. The program was developed by mapping assessment tasks to a research capabilities framework that was in turn scaffolded to different levels of Miler's pyramid. The curriculum and assessments were integrated with the science, clinical, and professional aspects of the medical course. The progressive longitudinal development of research skills, with feedback and academic mentoring, culminated in the students' capacity to undertake an independent research project. Designing an assessment program for learning encouraged students to develop their research capacity by involving them in their learning.

Background: Dietary modification is critical in the self-management of chronic kidney disease. The present study describes the accuracy, quality and health literacy demand of renal diet information for adults with kidney disease obtained from the Internet and YouTube (www.youtube.com). Methods: A comprehensive content analysis was undertaken in April and July 2015 of 254 eligible websites and 161 YouTube videos. The accuracy of the renal diet information was evaluated by comparing the key messages with relevant evidence-based guidelines for the dietary management of people with kidney disease. The DISCERN tool (www.discern.org.uk) was used to evaluate the quality of the material. Health literacy demand was evaluated using the Patient Education Material Assessment Tool (www.ahrq.gov/professionals/prevention-chronic-care/improve/self-mgmt/pemat/index.html) and seven validated readability calculators. Results: The most frequent renal diet topic found online was generic dietary information for people with chronic kidney disease. The proportion of renal diet information obtained from websites that was accurate was 73%. However, this information was mostly of poor quality with extensive shortcomings, difficult to action and written with a high health literacy demand. By contrast, renal diet information available from YouTube was highly understandable and actionable, although only 18% of the videos were accurate, and a large proportion were of poor quality with extensive shortcomings. The most frequent authors of accurate, good quality, understandable, material were government bodies, dietitians, academic institutions and medical organisations. Conclusions: Renal diet information found online that is written by government bodies, dietitians, academic institutions and medical organisations is recommended. Further work is required to improve the quality and, most importantly, the actionability of renal diet information found online.

Background: Dietary modification is an important component of the management of end stage kidney disease (ESKD). The diet for ESKD involves modifying energy and protein intake, and altering sodium, phosphate, potassium and fluid intake. There have been no comprehensive reviews to date on this topic. The aims of this integrative review were to (i) describe the methods used to measure dietary adherence (ii) determine the rate of dietary adherence and (iii) describe factors associated with dietary adherence in ESKD. Methods: The Web of Science and Scopus databases were searched using the search terms 'adherence' and 'end stage kidney disease'. Of the 787 potentially eligible papers retrieved, 60 papers of 24,743 patients were included in this review. Of these papers, 44 reported the rate of dietary adherence and 44 papers described factors associated with adherence. Results: Most of the evidence regarding dietary adherence is derived from studies of hemodialysis patients (72% of patients). The most common method of measuring dietary adherence in ES KD was subjective techniques (e.g. food diaries or adherence questionnaires). This was followed by indirect methods (e.g. serum potassium, phosphate or interdialytic weight gain). The weighted mean adherence rate to ESKD dietary recommendations was 31.5% and 68.5% for fluid recommendations. Adherence to protein, sodium, phosphate, and potassium recommendations were highly variable due to differences in measurement methods used, and were often derived from a limited evidence base. Socioeconomic status, age, social support and self-efficacy were associated with dietary adherence. However, factors such as taste, the impact of the diet on social eating occasions; and dietetic staffing also appear to play a role in dietary adherence. Conclusion: Dietary adherence rates in people with ESKD are suboptimal. Further research is required on dietary adherence in patients with ESKD from different social, educational, economic and ethnic

ATP release from urinary bladder is vital for afferent signaling. The aims of this study were to localize CALHM1 and pannexin-1 expression and to determine their involvement in mediating ATP release in the bladder. Gene expression by PCR and immunohistochemistry were performed in the porcine bladder. CALHM1 and pannexin-1 mediated ATP release in response to hypotonic solution (0.45% NaCl) induced stretch and extracellular Ca2+ depletion ([Ca2+]0) was measured in isolated urothelial, suburothelial and detrusor muscle cells. CALHM1 and pannexin-1 mRNA and immunoreactivity were detected in urothelial, suburothelial and detrusor muscle layers with a highest expression on urothelium. Hypotonic stretch caused a 2.7-fold rise in ATP release from all three cell populations (P < 0.01), which was significantly attenuated by the pannexin-1 inhibitor,10Panx1, and by CALHM1 antibody. Brefeldin A, a vesicular transport inhibitor, and ruthenium red, a non-selective CALHM1 channel blocker, also significantly inhibited stretch-mediated ATP release from urothelial cells. [Ca2+]0 caused a marked but transient elevation of extracellular ATP level in all three cell populations. CALHM1 antibody and ruthenium red inhibited [Ca2+]0-induced ATP release from urothelial cells, but their effects on suburothelial and detrusor cells was insignificant. 10Panx1 showed no significant inhibition of [Ca2+]0-induced ATP release in any types of cells. The results presented here provide compelling evidence that pannexin-1 and CALHM1 that are densely expressed in the porcine bladder function as ATP release channels in response to bladder distension. Modulation of extracellular Ca2+ may also regulate ATP release in the porcine bladder through voltage gated CALHM1 ion channels.

Background: This study aimed to assess and compare health literacy levels in a range of university-based health students. Methods: A survey containing the Health Literacy Questionnaire (HLQ) was administered to students enrolled in university-based medical, allied health or nursing degree programs. The HLQ scores and scale scores were compared across student groups. Results: In total, 374 students (24% response rate) with a median age of 25 years (range: 17-61 years), returned completed surveys. Three students who did not identify their degree programs were excluded from the final analysis which included 371 respondents; 242 graduate-entry medical students (65%), 67 allied health students (18%) and 62 nursing students (17%). Overall, the medical students had the highest score for seven of the nine HLQ scales; while the nursing students had the lowest score for all of the nine HLQ scales. Conclusion: These results show that health literacy profiles are different across student groups. In order to provide excellent patient-centred care, and to successfully look after their own health, a high level of health literacy is required by future health professionals. Health literacy training modules, tailored according to the different needs of the student groups, should therefore be included in university-based health professional degree programs.

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.

of a poster presentation at the 2016 National Medicines Symposium, 19-20 May, Canberra, Australia.

The role of subclinical infection in patients with urge incontinence has been largely ignored. The aim of this study was to test for the presence of intracellular bacteria in exfoliated urothelial cells obtained from the urine of patients with detrusor overactivity or mixed incontinence +/- a history of UTI, and compare this to a control group of patients with stress incontinence and no history of infection. Bacterial cystitis was assessed by routine microbiology and compared to microscopic analysis of urine by Wright staining. Subsequent analysis of urothelial cells by confocal microscopy was performed to determine the existence of intracellular bacteria. Bacterial cystitis was seen in 13% of patients based on routine microbiology. Wright staining of concentrated urothelial cells demonstrated the presence of bacteria in 72% of samples. Filamentous bacterial cells were observed in 51% of patients and were significantly more common in patients with detrusor overactivity. Intracellular Escherichia coli were observed by confocal microscopy. This study supports the possibility that a subset of patients with urge incontinence may have unrecognised chronic bacterial colonisation, maintained via an intracellular reservoir. In patients with negative routine microbiology, application of the techniques used in this study revealed evidence of infection, providing further insights into the aetiology of urge incontinence.

of an oral presentation at the 51st Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 7-9 September 2015, National Convention Centre, Canberra, Australia.

of an oral presentation at the 51st Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 7-9 September 2015, National Convention Centre, Canberra, Australia.

of an oral presentation at the 51st Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 7-9 September 2015, National Convention Centre, Canberra, Australia.

Inadequate health literacy in people with chronic kidney disease (CKD) is associated with poorer disease management and greater complications. There are limited data on the health literacy deficits of people with CKD. The aim of this study was to investigate the types and extent of health literacy deficits in patients with CKD using the multidimensional Health Literacy Management Scale (HeLMS) and to identify associations between patient characteristics and the domains of health literacy measured by the HeLMS. Invitations to participate were sent to patients with CKD attending the renal unit of a regional Australian hospital. These patients included predialysis, dialysis (peritoneal and hemodialysis), and kidney transplant patients. This study identified that inadequate health literacy-especially in the domains relating to attending to one's health needs, understanding health information, social support, and socioeconomic factors-was common. Male gender and education level were significantly associated with inadequate health literacy. The type and extent of health literacy deficits varied among CKD groups, and transplant patients had more deficits than other CKD patient groups. This study provides useful information for health professionals treating patients with CKD, especially with regard to the design of self-management interventions and health information.

of a poster that presented at the 50th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 25-27 August 2014, Melbourne Convention and Exhibition Centre Melbourne, Australia.

of a oral presentation at the 50th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 25-27 August 2014, Melbourne Convention and Exhibition Centre Melbourne, Australia.

of Oral Presentations at the 2014 AUGS-IUGA Scientific Meeting, July 22-26, 2014, Washington DC.

ATP is an important mediator of urgency in women with detrusor overactivity (DO). In order to understand how different degrees of bladder stretch elicited ATP release in DO patients compared with controls, sequential aliquots were collected during cystometry and ATP release was measured at each degree of bladder filling, in female patients with DO and controls. In both DO and control groups, ATP release was induced during bladder filling, suggesting that stretch stimulated further ATP release. However, the luminal ATP concentrations were already high at early filling stage (200 mL), which was even greater than those at the later filling stages (400 mL and maximum cystometric capacity, MCC), indicating that a substantial ATP release has been induced during early filling (200 mL) in both DO and controls. In DO, ATP release at 200 mL was significantly higher in those with low first desire to void (FDV) (≤200 mL) than in those with higher FDV (>200 mL); this may suggest that ATP release at early stretch may play an important role in urgency (early sensation) in DO. ATP concentrations remained unchanged after voiding, suggesting that voiding did not further induce ATP release into intraluminal fluid.

Inflammation is an important contributor to the aetiology of a number of bladder dysfunctions including interstitial cystitis, painful bladder syndrome, and overactive bladder. The aim of this study was to examine the effects of inflammatory mediators on urothelial ATP release. Human urothelial RT4 cells were exposed to normal buffer or varying concentrations of inflammatory mediators (bradykinin, histamine, and serotonin) in the presence or absence of hypotonic stretch stimuli (1 : 2 dilution of Krebs-Henseleit buffer). Others have demonstrated that bradykinin increased stretch-induced ATP release; however, we observed no change in control or stretch-induced ATP release with bradykinin. Pretreatment of RT4 cells with histamine or serotonin decreased stretch-induced ATP release (P = 0.037, P = 0.040, resp.). Previous studies have demonstrated increased ATP release in response to inflammation utilising whole bladder preparations in contrast to our simple model of cultured urothelial cells. The current study suggests that it is unlikely that there is a direct interaction between the release of inflammatory mediators and increased ATP release, but rather more complex interactions occurring in response to inflammation that lead to increased bladder sensation.

AIMS: In the bladder, ATP is an important signaling molecule, which is released by bladder stretch and acid. We hypothesized that ATP might play a unique role in patients with OAB, characterized by low bladder volumes at first desire to void (FDV) and maximal cystometric capacity (MCC) and symptoms of frequency/urgency [mild bladder pain syndrome (BPS)]. Our aim was to investigate the correlation between ATP release and urodynamic parameters, as well as urine pH, in OAB patients. METHODS: Routine cystometry was performed in a consecutive series of 249 women. The voided urodynamic fluid (VUF) was stored at -20°C and ATP measured using bioluminescence. Catheter urine was collected for pH measurement. Correlations between two factors were tested by linear regression analysis. RESULTS: Subjects with urinary tract infection, voiding dysfunction, and detrusor overactivity (DO) were excluded. For OAB patients (n = 25), there was an inverse correlation between ATP concentration in VUF and FDV (r(2) = 0.25; P = 0.01) but not MCC. This was not seen in controls (n = 69). In OAB, but not controls, there was a significant reverse correlation (r(2) = 0.16; P = 0.047) between ATP in VUF and urine pH. Urine pH was not significantly correlated with MCC in either group. CONCLUSIONS: In OAB patients, ATP is an important factor for initial perception of need to urinate (as indicated by FDV). This is similar to our previous findings in patients with DO, suggesting that ATP may mediate initial afferent sensation in patients with bladder dysfunctions characterized by urgency. ATP release was also strongly affected by urine pH, in patients with OAB (at FDV). Neurourol. Urodynam.