Urothelial cells may indicate underlying bacteriuria in pregnancy at term: a comparative study.

BACKGROUND: Urinary tract infection is common in pregnancy. Urine is sampled from by mid-stream collection (MSU). If epithelial cells are detected, contamination by vulvo-vagial skin and skin bacteria is assumed. Outside pregnancy, catheter specimen urine (CSU) is considered less susceptible to contamination. We compared MSU and CSU methods in term pregnancy to test these assumptions. METHODS: Healthy pregnant women at term gestation (n = 32, median gestation 38 + 6 weeks, IQR 37 + 6-39 + 2) undergoing elective caesarean section provided a MSU and CSU for paired comparison that were each analysed for bacterial growth and bladder distress by fresh microscopy, sediment culture and immunofluorescent staining. Participants completed a detailed questionnaire on lower urinary tract symptoms. Epithelial cells found in urine were tested for urothelial origin by immunofluorescent staining of Uroplakin III (UP3), a urothelial cell surface glycoprotein. Urothelial cells with closely associated bacteria, or "clue cells", were also counted. Wilcoxons signed rank test was used for paired analysis. RESULTS: Women reported multiple lower urinary tract symptoms (median 3, IQR 0-8). MSU had higher white blood cell counts (median 67 vs 46, z = 2.75, p = 0.005) and epithelial cell counts (median 41 vs 22, z = 2.57, p = 0.009) on fresh microscopy. The proportion of UP3+ cells was not different (0.920 vs 0.935, z = 0.08, p = 0.95), however MSU had a higher proportion of clue cells (0.978 vs 0.772, z = 3.17, p = 0.001). MSU had more bacterial growth on sediment culture compared to CSU specimens (median 8088 total cfu/ml vs 0, z = 4.86, p = 0.001). Despite this, routine laboratory cultures reported a negative screening culture for 40.6% of MSU specimens. CONCLUSION: Our findings have implications for the correct interpretation of MSU findings in term pregnancy. We observed that MSU samples had greater bacterial growth and variety when compared to CSU samples. The majority of epithelial cells in both MSU and CSU samples were urothelial in origin, implying no difference in contamination. MSU samples had a higher proportion of clue cells to UP3+ cells, indicating a greater sensitivity to bacterial invasion. Urinary epithelial cells should not be disregarded as contamination, instead alerting us to underlying bacterial activity.

Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection.

The development of new modalities for high-efficiency intracellular drug delivery is a priority for a number of disease areas. One such area is urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration. Meanwhile, oral antibiotics may also exacerbate antimicrobial resistance and cause systemic side effects. Using a human urothelial organoid model, we tested the ability of novel ultrasound-activated lipid microbubbles to deliver drugs into the cytoplasm of apical cells. The gas-filled lipid microbubbles were decorated with liposomes containing the non-cell-permeant antibiotic gentamicin and a fluorescent marker. The microbubble suspension was added to buffer at the apical surface of the bladder model before being exposed to ultrasound (1.1 MHz, 2.5 Mpa, 5500 cycles at 20 ms pulse duration) for 20 s. Our results show that ultrasound-activated intracellular delivery using microbubbles was over 16 times greater than the control group and twice that achieved by liposomes that were not associated with microbubbles. Moreover, no cell damage was detected. Together, our data show that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.

Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product designs.

OBJECTIVES: To compare the performance and cost-effectiveness of the key absorbent product designs to provide a more solid basis for guiding selection and purchase. Also to carry out the first stage in the development of a quality of life (QoL) instrument for measuring the impact of absorbent product use on users' lives. DESIGN: Three clinical trials focused on the three biggest market sectors. Each trial had a similar crossover design in which each participant tested all products within their group in random order. SETTING, PARTICIPANTS AND INTERVENTIONS: In Trial 1, 85 women with light urinary incontinence living in the community tested three products from each of the four design categories available (total of 12 test products): disposable inserts (pads); menstrual pads; washable pants with integral pad; and washable inserts. In Trial 2a, 85 moderate/heavily incontinent adults (urinary or urinary/faecal) living in the community (49 men and 36 women) tested three (or two) products from each of the five design categories available (total of 14 test products): disposable inserts (with mesh pants); disposable diapers (nappies); disposable pull-ups (similar to toddlers' trainer pants); disposable T-shaped diapers (nappies with waist-band); and washable diapers. All products were provided in a daytime and a (mostly more absorbent) night-time variant. In these first two trials, the test products were selected on the basis of data from pilot studies. In Trial 2b, 100 moderate/heavily incontinent adults (urinary or urinary/faecal) living in 10 nursing homes (27 men and 73 women) evaluated one product from each of the four disposable design categories from Trial 2a. Products were selected on the basis of product performance in Trial 2a and, again, day time and night-time variants were provided. The first phase of developing a QoL tool for measuring the impact of using different pad designs was carried out by interviewing participants from Trials 1 and 2a. MAIN OUTCOME MEASURES: Product performance (e.g. comfort, discreetness) was characterised using a weekly validated questionnaire. A daily pad change and leakage diary was used to record severity of leakage, numbers of laundry items and pads. Skin health changes were recorded weekly. At a final interview preferences were ranked, acceptability of each design recorded, and overall opinion marked on a visual analogue scale (VAS) of 0-100 points. This VAS score was used to estimate cost-effectiveness. In addition, a timed pad changing exercise was conducted with 10 women from Trial 2b to determine any differences between product designs. RESULTS: Disposable inserts are currently the mainstay of management for lightly incontinent women (Trial 1) and they were better for leakage and other variables (but not discreetness) and better overall than the other three designs. However, some women preferred menstrual pads (6/85) or washable pants (13/85), both of which are cheaper to use. Washable inserts were worse both overall and for leakage than the other three designs (72/85 found them unacceptable). For disposable inserts and disposable diapers, findings from the community (Trial 2a) and nursing home trials (Trial 2b) were broadly similar. Leakage performance of disposable inserts was worse than that of the other designs for day and night. Pull-ups were preferred over inserts for the daytime. The new T-shaped diaper was not better overall than the traditional disposable one. However, there were important differences in performance and preference findings for men and women from both trials. Pull-ups (the most expensive) were better overall than the other designs for women during the day and for community-dwelling women during the night. Although disposable diapers were better for leakage than disposable inserts (the cheapest), women did not prefer them (except in nursing homes at night), but for men the diapers were better both overall and for leakage and were the most cost-effective design. No firm conclusions could be drawn about the performance of designs for faecal incontinence. Nursing home carers found pull-ups and inserts easier to apply (in the standing position) and quicker (in the pad change experiment) than the diaper designs; the ability to stand was associated with preference for pull-ups or inserts. The T-shaped diaper was not easier or quicker to change than the diaper. The washable products (Trial 2a) gave diverse results: they were better for leakage at night, but were worse overall for daytime than the other designs. Three-quarters of the women (27/36) found them unacceptable, but nearly two-thirds of men (31/49) found them highly acceptable at night. Findings from the two community trials (Trials 1 and 2a) showed that there were many practical problems in dealing with washable products but, together with the less effective and less expensive products, such as menstrual pads, they were more acceptable at home (and, in the case of washables, at night). This suggests that cost-effective management may involve combining products by using more effective (for a given user) but more expensive designs (e.g. pull-ups) when out and less effective but less expensive designs when at home. The interviews examining the impact of pad use on QoL provided themes and domains that can be further developed into a tool for further evaluation of absorbent products. CONCLUSIONS: This study showed that there were significant and substantial differences between the designs of absorbent products and for moderate/heavy incontinence some designs are better for men/women than others. There was considerable individual variability in preferences and cost-effective management may best be achieved by allowing users to choose combinations of designs for different circumstances within a budget. Further research is needed into the feasibility of providing choice and combinations of designs to users, as well as into the development of more effective washables and of specifically male disposable products. QoL measurement tools are needed for users of absorbent products, as are clinical trials of designs for community-dwelling carer-dependent men and women with moderate/heavy incontinence.

Autonomic side effects of Botulinum toxin Type B intravesical injections: report of 4 cases and review of the literature.

Recently, intravesical injections of Botulinum toxin type B (BT-B) have been trialled in an attempt to treat detrusor overactivity. Use of Botulinum toxin A (BT.-A), for the same in the past, has been quite successful without many reported side effects. Soon after commencing the clinical use of BT-B, a side effect profile was noticed not reported with BT-A. A total of 20 patients with refractory detrusor overactivity were included in this randomized, double blind, placebo controlled, cross over trial. As per protocol, 5000 MU (1 ml) BT-B diluted to a volume of 20 mls with normal saline were injected in 10 different sites into the detrusor, sparing the trigone. We report four cases of autonomic side effects after these injections which strongly suggest clinically relevant systemic spread of the toxin.

Tolterodine: a safe and effective treatment for older patients with overactive bladder.

OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age > or =65 years) with symptoms of urinary urgency, increased frequency of micturition (> or =8 micturitions/24 hours), and/or urge incontinence (> or =1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, > or =87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder.

The influence of age on isometric and isotonic rat detrusor contractions.

BACKGROUND: Reductions in detrusor shortening velocity and detrusor contractility have been observed in association with aging. The reasons for these changes are unclear. METHODS: We examined the isometric and isotonic responses of detrusor, taken from the bladder body, to adenosine 5'-triphosphate (ATP), noradrenaline (NA), serotonin, and acetylcholine (Ach) in vitro, using bladders from young (30 days) and old (365 days) Sprague-Dawley rats, to determine whether there were any significant age-related differences. RESULTS: Isometric contractions with ATP at doses of 10(-3) to 10(-2) molar concentrations produced greater contractile forces in old rats when compared to young rats (p = .0136 at 10(-2) mole of ATP). Isotonic contractions at similar concentrations also produced significant differences between the young and the old rats, the latter being faster (p = .0225). Isometric contraction with noradrenaline produced significant differences between young and old rats, the latter being stronger. This became apparent at 10(-4) molar concentration of noradrenaline (p = .0043). Isometric contractions with serotonin also produced significantly greater contractions in the old rats when compared to young rats. The differences became apparent at 10(-4) molar concentration of serotonin (p = .045). There were no age-related differences in isotonic and isometric contractile responses to acetylcholine in the doses used in our experimental setup. CONCLUSIONS: Age-related differences in isometric function were detected in response to ATP, NA, and serotonin. Differences in isotonic function were only found in response to ATP and Ach.

Cross-infection between animals and man: possible feline transmission of Staphylococcus aureus infection in humans?

An outbreak of epidemic methicillin-resistant Staphylococcus aureus occurred on a rehabilitation geriatric ward. Intensive screening of patients and staff revealed an unusually high carriage rate in the nursing staff (38%), thought to be related to a ward cat which was heavily colonized from the environment. Infection control measures and removal of the cat led to rapid resolution of the outbreak.

Twelve-month treatment of overactive bladder: efficacy and tolerability of tolterodine.

CONTEXT: Tolterodine is a bladder-selective antimuscarinic agent designed for the treatment of overactive bladder. Traditional antimuscarinic therapies are poorly tolerated due to a high incidence of anticholinergic adverse events and consequently few patients remain on long term therapy. OBJECTIVE: To evaluate the long term efficacy and tolerability of tolterodine in patients with symptoms of overactive bladder. DESIGN: Twelve-month open-label extension of 4 randomised, placebo-controlled, double-blind, multinational, multicentre trials of 4 weeks' duration. PATIENTS: 714 patients (aged 18 to 92 years) with symptoms of overactive bladder who completed the double-blind portion of the studies. INTERVENTION: Tolterodine 2 mg twice daily for up to 12 months. MAIN OUTCOME MEASURES: Micturition diary variables: number of micturitions per 24 hours, number of urge incontinence episodes per 24 hours, mean urine volume voided per micturition. Safety variables: adverse events, study discontinuation rate. RESULTS: A total of 441 patients (62%) completed 12 months' open-label treatment with tolterodine, which significantly reduced the number of micturitions per 24 hours [mean change -2.4, 95% confidence interval (CI) -2.7 to -2.2, median change -20%, p < 0.0001] and number of urge incontinence episodes per 24 hours (mean change -1.3, 95% CI -1.6 to -1.0, median change -74%, p < 0.0001), while the mean volume voided per micturition was significantly increased (+33 ml, 95% CI +28 to +38, median change +18%; p < 0.0001). 41% of patients reported dry mouth (27% mild, 10% moderate, 3% severe). Dosage reduction to 1 mg twice daily was required in 23% of patients. 15% of patients withdrew from the study due to adverse events, with 5% having associated dry mouth. CONCLUSIONS: The high percentage of patients completing 12 months' treatment indicates that tolterodine is an effective and well tolerated agent for long term treatment of overactive bladder.

Overactive bladder: special considerations in the geriatric population.

Overactive bladder (OAB) is a highly prevalent condition among older patients, and its presence is associated with the use of substantial healthcare resources and economic costs. Within the next 30 years, it is expected that the demand for services related to OAB will increase dramatically. Treatment of OAB is challenging and depends on several factors, including the age of the patient, cognitive functioning, and the degree of mobility. Pharmacotherapy, such as the use of tolterodine and oxybutynin, is a viable option for the treatment of OAB, and muscarinic antagonists are commonly used. The efficacy of an agent may differ in older patients compared with younger ones. In addition, certain side effects can be particularly troublesome in the geriatric population. A retrospective analysis of a large managed care database showed an age-related increase in the number of women seeking care for OAB. Caring for incontinent patients in the long-term care setting was shown to result in substantial additional costs, which were higher in those with more frequent incontinent episodes. Prompted voiding may be effective in reducing the number of incontinent episodes for those in institutionalized care; however, this practice is labor intensive and generally is only effective in 40% of cases. Moreover, assistance with prompted voiding must be maintained continuously. Future research should focus on defining the most cost-effective methods of treating OAB in the long-term care setting.

Terodiline with bladder retraining for treating detrusor instability in elderly people.

OBJECTIVE: To compare terodiline with bladder retraining against placebo with bladder retraining in the treatment of detrusor instability in frail elderly patients. DESIGN: Randomised, double blind, parallel group study. Treatment lasted for six weeks. Frequency of micturition and episodes of incontinence recorded on diary chart by patients. SETTING: Incontinence clinic and a geriatric day hospital at two teaching hospitals. PATIENTS: 37 frail but ambulant patients, mean (range) age 80.4 (70-89) years with urinary frequency and urge incontinence, due to detrusor instability. Two patients withdrew before the first assessment (one in each group) and one could not complete the diary chart (placebo group). INTERVENTIONS: 19 patients received bladder retraining and terodiline 25 mg daily and 18 bladder retraining and placebo. MAIN OUTCOME MEASURES: Change in urinary frequency and number of episodes of incontinence after six weeks' treatment. Patient's subjective evaluation of symptoms. RESULTS: Little difference was found in the results of treatment with terodiline and placebo. The change in episodes of incontinence per 24 hours was no different in the two groups (95% confidence interval -0.6 to 1.2; p = 0.75) and the difference between treatments in the change in frequency of micturition per 24 hours (-0.2) was not significant (-1.1 to 1.2; p = 0.76). Ten patients taking terodiline thought they had improved compared with seven receiving placebo; this difference was not significant. CONCLUSION: Although the number of patients in each group was small and may have been insufficient to detect a drug effect, the possible benefit of terodiline is likely to be small.

Rapid urinalysis assays for the diagnosis of urinary tract infection.

Urinary tract infection (UTI) in premenopausal women is a frequent complaint in general practice. UTI is usually diagnosed on the basis of clinical symptoms and the use of one or more laboratory tests, the most common being rapid urinalysis reagent assays (urine dip) or midstream urine culture. In order to correlate the leucocyte esterase results of a rapid urinalysis assay with direct urine microscopy for pyuria, undiluted non-centrifuged urine samples from 206 volunteer female healthcare professionals were subjected to analysis using direct urine microscopy using a counting chamber and a rapid urinalysis assay. Of the 206 specimens, 74 were positive for leucocyte esterase using the rapid urinalysis assay, and 39 specimens demonstrated significant pyuria (greater than or equal to 10 leucocytes/microl) on direct microscopy. When the leucocyte esterase results were correlated with the direct urine microscopy results, an assay reading of 15 leucocytes/microl ('trace' on the visual scale) had a sensitivity of 91%, specificity of 79%, positive predictive value of 53% and a negative predictive value of 97%. An assay reading of 25 leucocytes/microl ('+' on the visual scale) or greater had a sensitivity of 63%, specificity of 95%, positive predictive value of 75% and a negative predictive value of 91%. In premenopausal, non-pregnant females, a rapid urinalysis assay result of 25 leucocytes/microl or greater will predict significant pyuria on urine microscopy with reasonable confidence, thereby reducing the need for more costly urine cultures.

A multicentre comparative evaluation of catheter valves.

Catheter valves are an alternative to leg bags for urine drainage, but no studies have yet been published which have compared the performance of different valves. This study was undertaken to evaluate the performance of the seven catheter valves available on the UK market in April 1996. The study was carried out by the Continence Products Evaluation (CPE) Network funded by the Medical Devices Agency (Department of Health). Each valve type was tested for 1 week by 19-36 cognitively unimpaired and manually dextrous subjects recruited from 11 test centres. At the end of each week, subjects completed an evaluation form (based on a three-point rating scale) to record product performance. The same catheter valves were also tested for ease of opening/closing by 33 subjects (mostly catheter users) who had some manual impairment. Performance scores varied widely between products. It was found that, to be successful, a valve needs to be easy to manipulate, leak-free, comfortable and inconspicuous. Prescribers need to be aware of the strengths and limitations of different valves for appropriate product selection.

Aberrant Ca2+ oscillations in smooth muscle cells from overactive human bladders.

Overactive bladder (OAB) syndrome is highly prevalent and costly, but its pathogenesis remains unclear; in particular, the origin of involuntary detrusor muscle activity. To identify the functional substrate for detrusor muscle overactivity, we examined intracellular Ca(2+) oscillations in smooth muscle cells from pathologically overactive human bladders. Basal cytoplasmic Ca(2+) concentration was elevated in smooth muscle cells from overactive bladders. Unprovoked, spontaneous rises of Ca(2+) were also identified. These spontaneous Ca(2+) oscillations were Ca(2+)-dependent, sensitive to L-type Ca(2+) channel antagonist verapamil and also attenuated by blocking SR Ca(2+) reuptake. The fraction of spontaneously active cells was higher in cells from overactive bladders and the magnitude of spontaneous Ca(2+) oscillations also greater. Spontaneous action potentials or depolarising oscillations were also observed, associated with Ca(2+) rise; with a higher percentage of cells from idiopathic OAB, but not in neurogenic OAB. Low concentrations of NiCl(2) attenuated both spontaneous electrical and Ca(2+) activation. This study provides the first evidence that spontaneous, autonomous cellular activity-Ca(2+) and membrane potential oscillations, originates from detrusor smooth muscle in human bladders, mediated by extracellular Ca(2+) influx and intracellular release. Such cellular activity underlies spontaneous muscle contraction and defective Ca(2+) activation contributes to up-regulated contractile activity in overactive bladders.

Case series data to encourage randomized trials of bladder retraining compared to antimuscarinic agents.

PURPOSE: This study was designed to test the power potential of a number of different clinical trial designs that could be deployed to test the efficacy of an antimuscarinic drug against bladder retraining. MATERIALS AND METHODS: This was an observational cohort study. Data were collected prospectively from patients treated for an overactive bladder by antimuscarinic agents with bladder retraining, or by bladder retraining alone. At initiation and at followup data on frequency, incontinence, urgency and urge incontinence were collected. Data from visits up to 16 weeks of treatment were analyzed using the parametric methods.708 patients were studied, 44 males and 664 females, and their mean age was 54 (sd 22). 52 patients used pure bladder retraining and 656 used bladder retraining and an antimuscarinic agent. The drug was oxybutynin, tolterodine or imipramine combined with oxybutynin or tolterodine as combination therapy. RESULTS: A between groups analysis demonstrated that bladder retraining was associated with a greater improvement in urinary frequency compared to antimuscarinic therapy (Z = -4.6, 95% CI of difference -3.3, -1.4, p <0.001) whereas antimuscarinic therapy was associated with a greater improvement in incontinence compared to bladder retraining (Z = -2.6, 95% CI of difference -0.93, -0.27, p = 0.024). The within group change in incontinence episodes in the bladder retraining group did not appear to show an effect (95% CI of change -0.19, 0.43). A subgroup showing greatest DeltaInc was sought. Boxplots of DeltaInc against age group, sex and the grading of symptoms were examined for maximum effect. Female sex, age group of 50 or greater and patients describing urge incontinence demonstrated the greatest DeltaInc. Their mean daily frequency was 11.45 (sd 6.1) and incontinence 1.6 (sd 2.1). A sample with such characteristics would be most sensitive to treatment effect. The bladder retraining group had a higher daily frequency (Z = -3.2, p = 0.001, 95% CI for bladder retraining 10 to 11, 95% CI for antimuscarinic group 10 to 12) and a lower daily incontinence compared to the antimuscarinic group (Z = -3.4, p <0.001, 95% CI of median for bladder retraining 0.75, 0.85, 95% CI of median for antimuscarinic group 0.75, 1.75). CONCLUSIONS: Change in frequency is a poor outcome measure, DeltaInc is significantly superior. An antimuscarinic tested against bladder retraining, using DeltaInc for outcome, would probably compare favorably.