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Introduction: Vaginal estrogen is a treatment for genitourinary symptoms of menopause (GSM), which comprises vaginal atrophy and urinary dysfunction, including incontinence. Previous studies show that estrogen therapy promotes lactobacilli abundance and is associated with reduced GSM symptoms, including reduction of stress incontinence. However, detailed longitudinal studies that characterize how the microbiome changes in response to estrogen are scarce. We aimed to compare the vaginalmicrobiota of postmenopausal women, before and 12 weeks after vaginal estrogen cream. Methods: A total of 44 paired samples from 22 postmenopausal women with vaginal atrophy and stress incontinence were collected pre-vaginal estrogens and were compared to 12 weeks post-vaginal estrogen. Microbiota was characterized by 16S rRNA amplicon sequencing and biodiversity was investigated by comparing the alpha- and beta-diversity and potential markers were identified using differential abundance analysis. Results: Vaginal estrogen treatment was associated with a reduction in vaginal pH and corresponded with a significant reduction in alpha diversity of the microbiota. Healthy vaginal community state type was associated with lower mean pH 4.89 (SD = 0.6), in contrast to dysbiotic state which had a higher mean pH6.4 (SD=0.74). Women with lactobacilli dominant community pre-treatment, showed stable microbiota and minimal change in their pH. Women with lactobacilli deficient microbiome pre-treatment improved markedly (p = 0.004) with decrease in pH -1.31 and change to heathier community state types. Conclusion: In postmenopausal women with stress incontinence, vaginal estrogen promotes Lactobacillus and Bifidobacterium growth and lowers vaginal pH. Maximum response is seen in those with a dysbiotic vaginal microbiota pre-treatment. [ABSTRACT FROM AUTHOR]

Introduction: The main function of the urinary tract is to form an impermeable barrier against urinary solutes and bacteria. However, this barrier can be compromised by urinary tract infections, most commonly caused by uropathogenic Escherichia coli (UPEC). This can result in damage to the epithelial barrier, leading to decreased epithelial thickness, loss of tight junctions, loss of epithelial integrity, and apoptosis. Due to the rise in antimicrobial resistance, there is worldwide interest in exploring non-antibiotic agents as alternative therapy. Methods: Using the Madin-Darby canine kidney (MDCK) cell line, a widely accepted epithelial cell model for the urinary tract, and the UPEC strain UTI89, this paper aimed to investigate the impact of UPEC on cell integrity, permeability, and barrier functions, and determine whether cranberry, D-mannose and ibuprofen could counteract the effects induced by UPEC. Furthermore, the study examined the protective potential of these agents against UPEC-induced increase in reactive oxygen species (ROS) production and programmed death-ligand 1 (PD-L1) expression. Results: The results demonstrated that UTI89 caused a marked reduction in cell viability and monolayer integrity. Cranberry (3mg/mL) was protective against these changes. In addition, cranberry exhibited protective effects against UPEC-induced damage to cell barrier integrity, escalation of oxidative stress, and UPEC/TNFa-triggered PDL1 expression. However, no effect was observed for D-mannose and ibuprofen in alleviating UPEC-induced cell damage and changes in ROS and PD-L1 levels. Conclusion: Overall, cranberry, but not D-mannose or ibuprofen, has a protective influence against UPEC associated damage in urinary epithelial cells. [ABSTRACT FROM AUTHOR]

Introduction: Proteus mirabilis is a key pathobiont in catheter-associated urinary tract infections (CA-UTIs), which is well known to form crystalline biofilms that occlude catheters. Urease activity alkylates urine through the release of ammonia, consequentially resulting in higher levels of Mg2+ and Ca2+ and formation of crystals. In this study, we showed that N-acetyl cysteine (NAC), a thiol antioxidant, is a potent urease inhibitor that prevents crystalline biofilm formation. Methods: To quantify urease activity, Berthelot's method was done on bacterial extracts treated with NAC. We also used an in vitro catheterised glass bladder model to study the effect of NAC treatment on catheter occlusion and biofilm encrustation in P. mirabilis infections. Inductively-coupled plasma mass spectrometry (ICP-MS) was performed on catheter samples to decipher elemental profiles. Results: NAC inhibits urease activity of clinical P. mirabilis isolates at concentrations as low as 1 mM, independent of bacterial killing. The study also showed that NAC is bacteriostatic on P. mirabilis, and inhibited biofilm formation and catheter occlusion in an in vitro. A significant 4-8log10 reduction in viable bacteria was observed in catheters infected in this model. Additionally, biofilms in NAC treated catheters displayed a depletion of calcium, magnesium, or phosphates (>10 fold reduction), thus confirming the absence of any urease activity in the presence of NAC. Interestingly, we also showed that not only is NAC anti-inflammatory in bladder epithelial cells (BECs), but that it mutes its inflammatory response to urease and P. mirabilis infection by reducing the production of IL-6, IL-8 and IL-1b. Discussion: Using biochemical, microbiological and immunological techniques, this study displays the functionality of NAC in preventing catheter occlusion by inhibiting urease activity. The study also highlights NAC as a strong antiinflammatory antibiofilm agent that can target both bacterial and host factors in the treatment of CA-UTIs. [ABSTRACT FROM AUTHOR]

Objective: To quantitate the changes in stress urinary incontinence (SUI) outcome measures after 12 weeks of vaginal estriol cream in women with stress incontinence. Methods: A prospective multicentre observational study conducted in tertiary urogynaecology centers. Postmenopausal women with pure SUI or stress predominant mixed urinary incontinence (MUI), not receiving any other treatment for their incontinence were given written instructions regarding digital application of a standard dose of vaginal estriol cream. Outcomes were measured at baseline and 12 weeks. The primary objective outcome was vaginal pH. The primary subjective outcome was the stress domain of the Urogenital Distress Inventory‐6 (UDI‐6). The secondary objective outcome used was the erect cough stress test. Two quality of life questionnaires and two patient reported outcomes were also included. Results: The 46 postmenopausal recruits had a median age of 62.1 interquartile range (IQR 56.2–65.4). At follow up, the primary subjective outcome SUI domain [UDI‐6] significantly improved from 83.3 (IQR 50–100) to 33.3 (33.3–66.7, p ≤ 0.001) as did vaginal pH [from 5.1 (4.9–5.9) to 4.9 (4.6–5.0] p ≤ 0.001; 18/43 patients (42%) were dry on cough stress test. Conclusions: Twelve weeks of vaginal estriol cream significantly reduced symptoms of stress urinary incontinence in this sample of postmenopausal women. [ABSTRACT FROM AUTHOR]

A recurrent urinary tract infection (UTI) is a common debilitating condition whereby uropathogens are able to survive within the urinary tract. In this study, we aimed to determine if the common uropathogens Escherichia coli, Enterococcus faecalis, and Group B Streptococcus possessed virulence mechanisms that enable the invasion of urothelial cells. Urothelial cells were isolated from women with detrusor overactivity and recurrent UTIs; the intracellular localisation of the uropathogens was determined by confocal microscopy. Uropathogens were also isolated from women with acute UTIs and their intracellular localisation and virulence mechanisms were examined (yeast agglutination, biofilm formation, and haemolysis). Fluorescent staining and imaging of urothelial cells isolated from women with refractory detrusor overactivity and recurrent UTIs demonstrated that all three uropathogens were capable of intracellular colonisation. Similarly, the bacterial isolates from women with acute UTIs were also seen to intracellularly localise using an in vitro model. All Enterococcus and Streptococcus isolates possessed a haemolytic capacity and displayed a strong biofilm formation whilst yeast cell agglutination was unique to Escherichia coli. The expression of virulence mechanisms by these uropathogenic species was observed to correlate with successful urothelial cell invasion. Invasion into the bladder urothelium was seen to be a common characteristic of uropathogens, suggesting that bacterial reservoirs within the bladder contribute to the incidence of recurrent UTIs. [ABSTRACT FROM AUTHOR]

Overactive bladder (OAB) is a clinical syndrome defined by urinary urgency, increased daytime urinary frequency and/or nocturia, with or without urinary incontinence, that affects approximately 11% of the western population. OAB is accepted as an idiopathic disorder, and is charactersied clinically in the absence of other organic diseases, including urinary tract infection. Despite this, a growing body of research provides evidence that a significant proportion of OAB patients have active bladder infection. This review discusses the key findings of recent laboratory and clinical studies, providing insight into the relationship between urinary tract infection, bladder inflammation, and the pathophysiology of OAB. We summarise an array of clinical studies that find OAB patients are significantly more likely than control patients to have pathogenic bacteria in their urine and increased bladder inflammation. This review reveals the complex nature of OAB, and highlights key laboratory studies that have begun to unravel how urinary tract infection and bladder inflammation can induce urinary urgency and urinary frequency. The evidence presented in this review supports the concept that urinary tract infection may be an underappreciated contributor to the pathophysiology of some OAB patients. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: The continence dish has been a treatment option since 2002 for women with stress urinary incontinence (SUI) who decline surgery, but few quantitative objective efficacy data are published. We aimed to determine the efficacy and acceptability of this device for pure SUI or mixed incontinence (MUI). Methods: Prospective interventional cohort study of 100 women with SUI or stress-predominant MUI who were interested to use the device; International Consultation on Incontinence Questionnaire (ICIQ) was primary outcome measure; 24-h pad test and Incontinence Impact Questionnaire (IIQ) were secondary outcomes. Acceptability was determined by device retention for 4 weeks, adverse events and ability to self-insert the device. Results: Of 100 suitable women, 9 were not actually fitted, and 27 did not complete (acceptability: 64/100). The rate of adverse events was 7.7%, with 62.5% of users able to self-insert the device: 22 (34%) had pure SUI; 66% had MUI. In SUI, 68% were 'dry' on ICIQ median value 4.0 (IQR 2.5–8.5); 88% were dry on 24-h pad test (median 0.0, IQR 0.0–8.5). The "dry rate" was lower in MUI: 36% for ICIQ (median 9.0, IQR 5.0–15.0) and 62% for 24-h pad test (median 6.2, IQR 0.95–19.7). A "good" response on IIQ occurred in 88% of SUI and 69% of MUI. Conclusion: These new data showing strong objective benefits of the continence dish should be further validated by randomized trials, but this information should be made available to women seeking treatment options for SUI/MUI (particularly in view of concerns regarding mesh mid-urethral slings). [ABSTRACT FROM AUTHOR]

Patients undergoing chemotherapy with cyclophosphamide experience cystitis due to excretion of a toxic metabolite, acrolein. Cystitis, an inflammation of the bladder, is associated with damage to the integrity of the urothelial barrier. The purinergic P2X7 receptor (P2X7R) is increasingly recognized for its role in inflammation and cell death. P2X7R is expressed abundantly on the bladder urothelium. The aim of this study was to investigate the role of P2X7R in acrolein-induced inflammatory damage in primary cultured porcine bladder urothelial cells. Confluent urothelial cells in culture were treated with acrolein to induce damage; also, with the P2X7R selective antagonist, A804598. Cell viability assay, immunocytochemistry, and trans-epithelial electrical resistance (TEER) studies were carried out to investigate the effect of treatments on urothelial cell function. Acrolein induced a significant reduction in urothelial cell viability, which was protected by the presence of A804598 (10 µM). The urothelial barrier function, indicated by TEER values, was also significantly reduced by acrolein, whereas pre-incubation with P2X7R antagonist significantly protected the urothelial cell barrier from acrolein-induced TEER reduction. The structure of urothelial cell tight junctions was similarly impacted by acrolein treatment, showing the fragmentation of zona occludens-1 (ZO-1) immunoreactivity. Pre-treatment of cells with A804598 countered against the actions of acrolein and maintained ZO-1 expression level and cell structure. The damaging effect of acrolein on urothelial cells integrity could be impaired by inhibition of P2X7R, therefore P2X7R blockade may be a possible therapy in patients with bladder cystitis caused by cyclophosphamide treatment. [ABSTRACT FROM AUTHOR]

Inflammatory conditions of the urinary bladder have been shown to be associated with urothelial damage and loss of function. The purinergic P2X7 receptor has been implicated in several inflammatory conditions. The aim of this study was to investigate the role of the P2X7 receptor in acrolein-induced inflammatory damage using the porcine urinary bladder. For this purpose, an ex-vivo model of porcine urothelial damage induced by direct instillation of acrolein into the whole bladder lumen was used. To determine the role of the P2X7 receptor, the bladders were pre-incubated with a selective P2X7 receptor antagonist, A804598 (10 μM), for 1 h. The effects of the acrolein-induced urothelial damage on the bladder's function were assessed by examining the bladder wall contractile response, structure changes, apoptosis, and oxidative stress in the bladder tissues. The acrolein treatment led to significant damage to the urothelium histology, tight junction expression, and contractile responses. Acrolein also induced apoptosis in the mucosa layer. All these acrolein-induced responses were attenuated by pre-treatment with the P2X7 receptor antagonist A804598. Acrolein also significantly induced DNA oxidation in the submucosal layer; however, the P2X7 receptor antagonism did not show any protective effect towards the acrolein-induced oxidative stress. These findings suggested that the P2X7 receptor is involved in the acrolein-induced damage to the urothelium; therefore, the P2X7 receptor antagonists may be a new therapeutic option for the treatment of bladder inflammation. [ABSTRACT FROM AUTHOR]

Over 50% of women with detrusor overactivity (DO), who do not respond to therapy have been shown to have bacteriuria, which may stimulate the release of inflammatory cytokines than can enhance nerve signalling, leading to symptoms of urgency. This study made use of a consecutive series of urine samples collected from women with refractory DO, who participated in a clinical trial of rotating antibiotic therapy. The aim was to determine the effect of bacteriuria and antibiotic treatment on the levels of urinary cytokines, and to correlate the cytokine concentration with patient outcome measures relating to urgency or urge incontinence. The urinary cytokines chosen were IL-1α, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, CXCL10 (IP-10), MCP-1 and TNF-α. The presence of bacteriuria stimulated a significant increase in the concentrations of IL-1α (P 0.0216), IL-1 receptor antagonist (P 0.0264), IL-6 (P 0.0003), IL-8 (P 0.0043) and CXCL-10 (P 0.009). Antibiotic treatment significantly attenuated the release of IL-1α (P 0.005), IL-6 (P 0.0027), IL-8 (P 0.0001), IL-10 (P 0.049), and CXCL-10 (P 0.042), i.e. the response to the presence of bacteria was less in the antibiotic treated patients. Across the 26 weeks of the trial, antibiotic treatment reduced the concentration of five of the nine cytokines measured (IL-1α, IL-6, IL-8, IL-10 and CXCL-10); this did not reach significance at every time point. In antibiotic treated patients, the urinary concentration of CXCL-10 correlated positively with four of the six measures of urgency. This study has shown that cytokines associated with activation of the innate immune system (e.g. cytokines chemotactic for or activators of macrophages and neutrophils) are reduced by antibiotic therapy in women with refractory DO. Antibiotic therapy is also associated with symptom improvement in these women, therefore the inflammatory response may have a role in the aetiology of refractory DO. [ABSTRACT FROM AUTHOR]

Aim: Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. Methods: In a multicenter phase IIb double‐blinded randomized placebo‐controlled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24‐h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3‐day bladder diary and quality of life measures. Microbiological data were collected at all visits. Results: Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24‐h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. Conclusion: Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6‐month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment. [ABSTRACT FROM AUTHOR]

Aims: To quantify estriol serum concentrations in "new" and "chronic users" of topical estriol cream using quantitative liquid chromatography tandem mass spectrometry. Methods: In this singlecentre prospective observational study, postmenopausal women with urogynaecological complaints were enrolled: 40 had not used topical estriol previously ("new users") and 50 had been applying estriol cream for more than 12 weeks ("chronic users"). In "new users," serum estriol levels were measured at baseline and after 12 weeks use. Estriol cream 1 mg/g was used daily for 3 weeks, then twice weekly with applicator (group 1A) or digitally (group 1B) or three times per week digitally (group 1C). "Chronic users" applied the cream twice (n = 7) or three (n = 43) times per week. Serum samples were taken in the morning after using cream the previous night. The main outcome measures were estriol serum concentrations in "new" and "chronic users" of estriol cream. Results: Baseline serum estriol concentrations were less than 5 pmol/L in all 40 "new users." At 12 weeks, the 12‐hour serum estriol levels ranged from less than 5 to 494 pmol/L (median 22.8; Interquartile range [IQR] 9.2–108.5). Seven "new users" had levels more than 100 pmol/L. Most of the 50 "chronic users" also had 12‐hour levels less than 100 pmol/L (median 15.1 pmol/L [IQR 2.7–33.9]: three had levels more than 100 pmol/L. Conclusions: This study reports serum estriol concentrations in a large number of "new" and "chronic users" of vaginal estriol cream, employing a novel highly sensitive and specific technique. Overall, the results are reassuring: 87% had 12‐hour estriol levels less than 100 pmol/L. [ABSTRACT FROM AUTHOR]

Many cancer therapies operate by inducing double-strand breaks (DSBs) in cancer cells, however treatment-resistant cells rapidly initiate mechanisms to repair damage enabling survival. While the DNA repair mechanisms responsible for cancer cell survival following DNA damaging treatments are becoming better understood, less is known about the role of the epigenome in this process. Using prostate cancer cell lines with differing sensitivities to radiation treatment, we analysed the DNA methylation profiles prior to and following a single dose of radiotherapy (RT) using the Illumina Infinium HumanMethylation450 BeadChip platform. DSB formation and repair, in the absence and presence of the DNA hypomethylating agent, 5-azacytidine (5-AzaC), were also investigated using γH2A.X immunofluorescence staining. Here we demonstrate that DNA methylation is generally stable following a single dose of RT; however, a small number of CpG sites are stably altered up to 14 d following exposure. While the radioresistant and radiosensitive cells displayed distinct basal DNA methylation profiles, their susceptibility to DNA damage appeared similar demonstrating that basal DNA methylation has a limited influence on DSB induction at the regions examined. Recovery from DSB induction was also similar between these cells. Treatment with 5-AzaC did not sensitize resistant cells to DNA damage, but rather delayed recruitment of phosphorylated BRCA1 (S1423) and repair of DSBs. These results highlight that stable epigenetic changes are possible following a single dose of RT and may have significant clinical implications for cancer treatment involving recurrent or fractionated dosing regimens. [ABSTRACT FROM AUTHOR]

Urinary tract infection is often reported by people who perform clean intermittent self- catheterisation (CISC). This project aimed to assess the incidence of urinary tract infection, in those undertaking multiple catheter reuse versus single-use catheter, using a prospective randomised controlled trial, with crossover design. The burden of costs for the patient employing single-use catheters, compared to multiple reuse catheters was also examined. Eligible participants performing CISC were randomised to single-use or multiple reuse of catheters for eight weeks, then crossed over to the alternative for eight weeks. The primary outcome measure was the incidence of symptomatic urinary tract infection, determined by bacteria load in catheter specimens of urine collected at baseline and then every four weeks. Proven bacterial cystitis and asymptomatic bacteriuria was also determined. Measures of the fnancial impact of self-catheterisation were also collected. The 23 participants (average age 60 years) were 73% female. Self-catheterisation for post-operative retention was required for 10/23 (43%) of participants. At week eight, symptomatic urinary tract infection occurred in 20% of single- use, versus 17% in the multiple reuse group. The infection rate did not increase after crossover from single-use to multiple catheter reuse (p=0.26). Similarly, the incidence of pyuria in participants did not difer in the single or multiple reuse arm of the trial (p=0.75). The estimated annual cost of single- use CISC was more than 20 times higher than for multiple reuse. These data show no clinically apparent trend towards increased rates of UTI in participants who reused their CISC catheters. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Urinary urge incontinence is a chronic, debilitating condition that is difficult to treat. Patients refractory to standard antimuscarinic therapy often experience recurrent urinary tract infections (rUTIs). The microbiota of these refractory patients with rUTI remains unexplored.Methods: A midstream urine (MSU) sample was collected from patients with refractory urge incontinence and coexistent rUTI during acute symptomatic episodes. Culture-based diagnosis was performed using routine microbiological methods. Culture-independent profiling was performed using bacterial 16S RNA profiling. E. coli strain typing was performed by amplicon pyrosequencing of the fimH gene.Results: Over 2 years, 39 patients with refractory urge incontinence and coexistent rUTI were studied, yielding 9 severely affected cases. These 9 patients were carefully monitored for a further 2 years, resulting in the collection of 102 MSU samples, 70 of which were diagnosed as UTI (median of 8 UTIs/woman). Culture-independent analysis of 38 of these samples revealed the existence of a diverse urinary microbiota. Strain typing of E. coli identified instances of rUTI caused by the same persisting strain and by new infecting strains.Conclusions: Patients with refractory urge incontinence and coexistent rUTI possess a diverse urinary microbiota, suggesting that persistent bladder colonisation might augment the pathology of their chronic condition. [ABSTRACT FROM AUTHOR]

Aim: The mechanisms leading to the development of detrusor overactivity (DO) are still relatively poorly understood, however, animal studies suggest that atherosclerosis and reduced blood flow to the bladder may be one etiological pathway. Thus, the aim of this study was to evaluate signs of atherosclerosis in a large cohort of women with detrusor overactivity, using two precise measures of atherosclerotic vascular impairment, Ankle Brachial Index (ABI), and Brachial—ankle Pulse Wave Velocity (baPWV). Methods: A prospective cohort study measuring ABI and baPWV of women with DO and controls was conducted. The ABI and baPWV were measured using an automated oscillometric blood pressure machine, to evaluate the degree of atherosclerosis in patients with DO and controls. Associations between ABI and baPWV and important confounding variables were assessed by a linear regression model. Results: Ninety‐eight women with DO, and 98 controls without any symptoms of DO were studied. Multivariate analysis showed an increase in left baPWV of approximately 96 cm/s units of velocity (95%CI 20.65‐172.05, P = 0.01) is predicted significantly by the presence or absence of detrusor overactivity (as well by independent factors of age, diastolic blood pressure and body mass index). A similar effect was seen for right baPWV. Conclusions: On linear regression modeling, the presence of DO was a strong predictor for an increased PWV when controlling for age, BMI and diastolic blood pressure (DBP), thus supporting the hypothesis that atherosclerosis may contribute to the etiology of DO. [ABSTRACT FROM AUTHOR]

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 bladderinnervating 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. [ABSTRACT FROM AUTHOR]

Background and Aim: The few studies that have examined direct costs of faecal incontinence are limited in that they employed retrospective databases, postal surveys, and focused upon institutionalised patients or post partum women. The aim of the current study was to identify the direct pre‐treatment costs of faecal incontinence expended by a range of home dwelling patients and identify relationships between costs and severity of incontinence. Methods: Consecutive patients attending an outpatient clinic for treatment of faecal incontinence were interviewed using a questionnaire, modeled on the Dowel Bryant Incontinence Cost Index. The information collected included costs of: (i) basic personal hygiene: pads, laundry, wipes, cleansers; (ii) medication: loperamide, creams and stool bulking agents; and (iii) diagnostic: medical attendance, anorectal physiology, colonoscopy. Costs were broken down into personal expenses, government costs, and costs to health funds. A St Mark's Faecal Incontinence Severity Score was recorded. Results: A total of 100 consecutive patients consented (15 males, 85 females) mean age 70.8 (SD12) years. Mean St Mark's score was 12 (SD4.5). The median total patient cost was $437.72 AUD (range 0‐2807) per annum. Government costs were $537AUD (range 135‐1657), and health fund median $0 AUD (0‐1628). Incontinence severity correlated with personal expense only median $283.75AUD (range 0‐2350). The aged were more incontinent but costs did not increase in relation to age. Conclusion: Faecal incontinence results in a substantial financial burden for both patients and Government. Effective treatments which relieve the financial burden of faecal incontinence, are likely to be economically advantageous into the future for both patients and Government. [ABSTRACT FROM AUTHOR]

Integrins are transmembrane adhesion receptors that play an important role in hematopoiesis by facilitating interactions between hematopoietic cells and extracellular matrix components of the bone marrow and hematopoietic tissues. These interactions are important in regulating the function, proliferation, and differentiation of hematopoietic cells, as well as their homing and mobilization in the bone marrow. Not surprisingly altered expression and function of integrins plays a key role in the development and progression of cancer including leukemias.However, the regulation of integrin gene expression is notwell characterized and themechanisms bywhich integrin genes are disrupted in cancer remain unclear. Here we demonstrate for the first time that a key regulator of hematopoiesis, RUNX1, binds to and regulates the promoters of both the ITGA6 and ITGB4 genes in myeloid cells. The ITGA6 and ITGB4 integrin genes form the α6β4 integrin receptor. However, our data indicate that RUNX1 functions differently at these two promoters. RUNX1 regulates ITGA6 through a consensus RUNX1 binding motif in its promoter. In contrast, although the ITGB4 promoter is also activated by RUNX1, it does so in the absence of a recognized consensus RUNX1 binding motif. Furthermore, our data suggest that regulation of ITGB4 may involve interactions between the promoter and upstream regulatory elements. [ABSTRACT FROM AUTHOR]

Aims Although pelvic floor muscle training (PFMT) is effective for stress urinary incontinence (SUI), patients need to be motivated to obtain cure. An instrument to assess motivation in such patients was published in 2009: the Incontinence Treatment Motivation Questionnaire (ITMQ). The ITMQ consists of five domains: (i) positive attitudes toward PFMT; (ii) reasons for not doing PFMT; (iii) difficulties living with incontinence; (iv) desire for treatment; and (v) incontinence severity influencing motivation. The aim of the present study was to examine the relationship between ITMQ scores and treatment success. Methods After referral for PFMT, women with SUI completed the ITMQ. Pre- and post-treatment outcomes were the International Consultation on Incontinence Questionnaire (ICIQ) score and a 24-hr pad test. Correlations between ITMQ scores and baseline, as well as post-treatment change in ICIQ scores and pad test results were examined. Additionally, the demographics of non-participants, participants, and patients lost to follow-up were compared. Results Of 85 recruits, 18 did not complete the ITMQ, 14 were lost to follow-up, thus 53 completed the PFMT programme and undertook either one or both outcomes. Pre-treatment, severity on ICIQ correlated with total ITMQ (ρ = 0.33, P = 0.01). Post-treatment change in pad test was inversely correlated with Domain 2 (ρ = −0.33, P = 0.03). Conclusions The pre-treatment severity of incontinence was significantly associated with motivation for treatment. Unfortunately, post-treatment change correlated with only one domain of the questionnaire. Further modification of the ITMQ is envisaged. Neurourol. Urodynam. 36:316-321, 2017. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim: Subjectively and objectively assess stress urinary incontinence (SUI) symptoms before and after topical oestrogen therapy.Methods: A prospective study was performed in 3 centres in South-Africa, Australia and the Netherlands. Postmenopausal women with SUI were treated with topical oestriol cream for 6 weeks. The primary subjective outcome was the Patient's Global Impression of Improvement (PGI-I) scale. The primary objective outcome was vaginal pH. Secondary subjective outcomes were: the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form, the Incontinence Impact Questionnaire, the Urogenital Distress Inventory (UDI-6) and the most bothersome symptom approach. Secondary objective outcome was the erect cough pad test. Compliance was scored.Results: A total of 68 women were enrolled. Half of the participants reported improvement on the PGI-I scale after treatment. Vaginal pH was significantly lower after treatment (median 5.3 (interquartile range (IQR) 4.5-6.0) vs. 5.0 (4.4-5.4), p = 0.002). Improvement on the UDI stress domain was observed (p = 0.01). No statistically significant differences were found in the other subjective outcomes. Baseline and repeat cough pad tests demonstrated a wide variation with no significant difference. Compliance was high (median 100 (IQR 83-100%)).Conclusion: Topical oestriol cream during 6 weeks improved quality of life and vaginal pH but no other objective measures of incontinence. [ABSTRACT FROM AUTHOR]

Background One subjective long-term evaluation of the tension-free vaginal tape ( TVT) success rate in obese women showed a worse prognosis in the obese, but objective studies have been limited to short-term follow-up (less than two years). Aim To determine whether the long-term objective cure rate in obese/morbidly obese women who underwent TVT was reduced, compared to non-obese women (at five or more years). Materials and methods Body mass index ( BMI) was collected on patients undergoing TVT procedure. Recruited patients were asked to perform a 24 h pad test and complete an International Consultation on Incontinence Questionnaire Short Form ( ICIQ- SF) at five years postoperatively. Data was analyzed according to pre-operative urodynamic diagnoses and BMI, using 'routine' and 'strict' objective definitions of objective cure. Results At median follow-up of 64 months (interquartile range 58-80 months), 136 patients returned a pad test and ICIQ- SF. Using a routine definition of cure (pad test of ≤10 g in a 24 h period), 96% of patients were cured overall. The BMI results ( n = 119 patients) were stratified into ≤25, 25.1-35 and ≥35.1 kg/m2, which represented 41, 53 and 6% of patients, respectively. The routine cure rates for these three groups were 98, 97 and 71%, respectively ( P = 0.004). Conclusion Long-term objective outcomes of the TVT in morbidly obese women are significantly poorer than in women with a normal BMI. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess whether cystoscopy with diathermy for cystitis cystica in patients with recurrent urinary tract infection (UTI) is associated with decreased incidence of UTI. A retrospective 9-year audit was performed in a single urogynaecology centre. Patients with proven recurrent UTI and failed conservative therapy underwent cystoscopy with diathermy to cystitis cystica. The number of UTI’s 12- months pre and post cystoscopy was evaluated using women as their own controls with multivariant analysis of cofounding factors. Of 82 patients with recurrent UTI, 47 patients underwent cystoscopy with diathermy to cystitis cystica (median follow up 2 months [interquartile range, IQR6-31, one patient lost to follow up]). Pre-cystoscopy median UTI per annum was 3 per patient (IQR1-4). Post cystoscopy, median UTI for each woman was significantly reduced (median reduction -2[IQR-5-1], mean -2.14[95%CI -2.94, -1.34], P=<0.001). In the subgroup of patients who had previous vaginal mesh repair for prolapse (n=8) there was no significant benefit from diathermy (median reduction - 1.5[95%CI -0.988, 3.988], P=0.197). In conclusion, cystoscopy and diathermy of cystitis cystica was generally associated with significant reductions in UTI’s in the 12 months following diathermy [ABSTRACT FROM AUTHOR]

The aim of this study was to reassess symptoms and signs of asymptomatic rectocoele in women five or more years post initial diagnosis and to determine any factors associated with a worsened condition. Women diagnosed with asymptomatic demonstrable rectocoele and seen at one centre between 1992 and 1999, were recruited via letter, which included information about the study. Once consent was received, participants were sent the Birmingham Bowel and Urinary Symptoms Questionnaire and invited to attend for reassessment of their condition and examination. At this appointment, the main outcomes were the questionnaire, pelvic organ prolapse examination, and Baden-Walker scale. Of the 316 consecutive women diagnosed with asymptomatic rectocoele who were contacted, 130 letters were returned "address unknown", 18 declined to participate, 49 had died and 19 did not reply. Of 100 replies, 4/100 (4%) declined because they had had prolapse surgery, 96/100 (96%) returned the questionnaire, of whom 6/96 (6%) declined further consultation. Of the 90 remaining women who returned the questionnaire, 62/90 (69%) were examined at a median of 5.9 years (IQR 5.1 to 7.3) and 11 women had undergone prolapse surgery, leaving 51 women in the cohort. In 31/51 (61%) remaining patients, the rectocoele findings were unchanged: all remained asymptomatic; 20/51 (39%) had a more advanced rectocoele on examination but only 5/51 (9.8%) had developed overt symptoms. Rectocoele progression was not associated with age, body mass index, oestrogen status, pelvic floor muscle training, or a history of constipation. Rectocoele progression was associated with greater median bowel symptom scores on Birmingham Bowel and Urinary Symptoms Questionnaire 18.7 (8.2 to 23.7) than non-progression 12.3 (4.2 to 16.7), p=0.027. In most patients (89.2%) with asymptomatic rectocoele, symptoms and signs were unchanged at five years. [ABSTRACT FROM AUTHOR]

The genome has the ability to respond in a precise and co-ordinated manner to cellular signals. It achieves this through the concerted actions of transcription factors and the chromatin platform, which are targets of the signaling pathways. Our understanding of the molecular mechanisms through which transcription factors and the chromatin landscape each control gene activity has expanded dramatically over recent years, and attention has now turned to understanding the complex, multifaceted interplay between these regulatory layers in normal and disease states. It has become apparent that transcription factors as well as the components and modifiers of the epigenetic machinery are frequent targets of genomic alterations in cancer cells. Through the study of these factors, we can gain unique insight into the dynamic interplay between transcription factors and the epigenome, and how their dysregulation leads to aberrant gene expression programs in cancer. Here, we will highlight how these factors normally co-operate to establish and maintain the transcriptional and epigenetic landscape of cells, and how this is reprogramed in cancer, focusing on the RUNX1 transcription factor and oncogenic derivative RUNX1-ETO in leukemia as paradigms of transcriptional and epigenetic reprograming. [ABSTRACT FROM AUTHOR]

The link between obesity and stress urinary incontinence is well documented, and rates of both have increased steadily with time. Conservative therapies including pelvic floor muscle training and weight loss are the first-line treatments for women who are obese and have stress urinary incontinence. However, if weight loss cannot be achieved, if pelvic floor muscle training is ineffective, or if symptoms continue, patients and clinicians may consider surgery. Traditionally, surgeons have been hesitant to perform abdominal colposuspension, pubo-vaginal sling and the mid-urethral sling surgeries on women who are obese. This paper reports a systematic review of the efficacy of surgical management for women who are clinically obese and require surgery to treat stress urinary incontinence. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is a chosen treatment option for prostate cancer patients and while some tumours respond well, up to 50% of patients may experience tumour recurrence. Identification of functionally relevant predictive biomarkers for radioresponse in prostate cancer would enable radioresistant patients to be directed to more appropriate treatment options, avoiding the side-effects of radiotherapy. Methods: Using an in vitro model to screen for novel biomarkers of radioresistance, transcriptome analysis of a radioresistant (PC-3) and radiosensitive (LNCaP) prostate cancer cell line was performed. Following pathway analysis candidate genes were validated using qRT-PCR. The DNA repair pathway in radioresistant PC-3 cells was then targeted for radiation sensitization using the PARP inhibitor, niacinimide. Results: Opposing regulation of a DNA repair and replication pathway was observed between PC-3 and LNCaP cells from RNA-seq analysis. Candidate genes BRCA1, RAD51, FANCG, MCM7, CDC6 and ORC1 were identified as being significantly differentially regulated post-irradiation. qRT-PCR validation confirmed BRCA1, RAD51 and FANCG as being significantly differentially regulated at 24 hours post radiotherapy (p-value =0.003, 0.045 and 0.003 respectively). While the radiosensitive LNCaP cells down-regulated BRCA1, FANCG and RAD51, the radioresistant PC-3 cell line up-regulated these candidates to promote cell survival post-radiotherapy and a similar trend was observed for MCM7, CDC6 and ORC1. Inhibition of DNA repair using niacinamide sensitised the radioresistant cells to irradiation, reducing cell survival at 2 Gy from 66% to 44.3% (p-value =0.02). Conclusions: These findings suggest that the DNA repair candidates identified via RNA-seq hold potential as both targets for radiation sensitization and predictive biomarkers in prostate cancer. [ABSTRACT FROM AUTHOR]

Gynaecologists are becoming increasingly aware that women with a family history of prolapse are at an increased risk of prolapse refractory to treatment. In the past five years, several genetic mutations have been shown to correlate with increased prolapse susceptibility. These mutations can result in disordered collagen metabolism, which weaken the fascial support of the pelvic organs. This review examines the contemporary evidence regarding the role of collagen in prolapse. [ABSTRACT FROM AUTHOR]

A think tank was convened at the fourth ICI-RS meeting, which took place June 5-7, 2013 in Bristol UK, to consider current evidence and controversies surrounding the possible role of 'covert infection' in the pathophysiology of refractory detrusor overactivity (DO) and other lower urinary tract disorders (LUTD). The topic was chosen because several authors from different centers worldwide have recently published evidence which supports this concept. However, to date there is inconsistency regarding terminology and microbiological definitions, which were discussed by the participants. The mechanisms whereby infection/inflammation could actually promote aberrant detrusor contractions in the human remain controversial, and are more fully described in this report. Future requirements for research into this topic were outlined. Neurourol. Urodynam. 33:606-610, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Patient choice is important in choosing appropriate treatments. We aimed to determine patient treatment preferences for urodynamic stress incontinence and reasons for particular preferences. In a survey, based in three urogynaecology departments in two countries, women diagnosed with urodynamic stress incontinence were given: 1) a questionnaire eliciting current knowledge of available urodynamic stress incontinence treatments; 2) information sheets describing pelvic floor muscle training by physiotherapists, the tension-free vaginal tape, and open colposuspension, including success rates and complications; and 3) a questionnaire about the preferred treatment and the reasons for the particular choice. Pelvic floor muscle training was the preferred management choice of 68/104 (65%) of participants; tension-free vaginal tape, 27 (26%); and open colposuspension six (6%) participants. The information sheets were the main basis for the particular choice in 86/104 (83%) of women. For the participants who chose pelvic floor muscle training 34/68 (50%) reported non-invasiveness and low risk as the main reasons for that particular choice. For participants who chose tension-free vaginal tape, the main reason was that it was a minimally invasive procedure. [ABSTRACT FROM AUTHOR]

Introduction Many women with pelvic floor dysfunction are unable to voluntarily contract their pelvic floor muscles. This study hypothesised that women who cannot contract their pelvic floor muscles, despite specialised pelvic floor physiotherapy, are likely to have avulsion defect of the levator ani muscle, visible on 3-dimensional ultrasound. Methods Pelvic floor muscle strength was assessed by modified Oxford scale in all women presenting to a tertiary urogynaecology clinic with a main complaint of urinary incontinence ± pelvic organ prolapse. Women who could not contract their pelvic floor muscles ( PFM) after having training with a specialised pelvic floor physiotherapist, (modified Oxford score of 0 or 1), were invited to participate in 3-dimensional transperineal ultrasound. Results Of 625 women presenting with urinary incontinence and/or pelvic organ prolapse, 150 (24.0%) were unable to contract their PFM at initial assessment. After specialised pelvic floor physiotherapy, 20 of 150 (15.3%) could not contract and were termed 'noncontractors'. Of these, 12 agreed to participate in transperineal ultrasound. Levator avulsion defects were detected in 8 of 12 (66.7%). Conclusion Our results show that 67% of women who cannot contract their PFM despite physiotherapy have levator avulsion defects. The mechanism affecting the remaining 33% is yet to be discovered. [ABSTRACT FROM AUTHOR]

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 (r2 = 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 (r2 = 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. 32: 969-973, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Bacteriuria, or the presence of bacteria in urine, is associated with both asymptomatic and symptomatic urinary tract infection and underpins much of the dynamic of microbial colonization of the urinary tract. The prevalence of bacteriuria in dissimilar patient groups such as healthy adults, institutionalized elderly, pregnant women, and immune-compromised patients varies widely. In addition, assessing the importance of 'significant bacteriuria' in infected individuals represents a diagnostic challenge, partly due to various causal microorganisms, and requires careful consideration of the distinct etiologies of bacteriuria in different populations and circumstances. Recent molecular discoveries have revealed how some bacterial traits can enable organisms to grow in human urine, which, as a fitness adaptation, is likely to influence the progression of bacteriuria in some individuals. In this review, we comprehensively analyze currently available data on the prevalence of causal organisms with a focus on asymptomatic bacteriuria in dissimilar populations. We evaluate recent advances in the molecular detection of bacteriuria from a diagnostic viewpoint and briefly discuss the potential benefits and some of the challenges of these approaches. Overall, this review provides an update on the comparative prevalence and etiology of bacteriuria from both microbiological and clinical perspectives. [ABSTRACT FROM AUTHOR]