James Malone-Lee

Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms.

ABSTRACT Chronic lower urinary tract symptoms (LUTS), such as urgency and incontinence, are common, especially among the elderly, but their etiology is often obscure. Recent studies of acute urinary tract infections implicated invasion by Escherichia coli into the cytoplasm of urothelial cells, with persistence of long-term bacterial reservoirs, but the role of infection in chronic LUTS is unknown. We conducted a large prospective study with eligible patients with LUTS and controls over a 3-year period, comparing routine urine cultures of planktonic bacteria with cultures of shed urothelial cells concentrated in centrifuged urinary sediments. This comparison revealed large numbers of bacteria undetected by routine cultures. Next, we typed the bacterial species cultured from patient and control sediments under both aerobic and anaerobic conditions, and we found that the two groups had complex but significantly distinct profiles of bacteria associated with their shed bladder epithelial cells. Strikingly, E. coli, the organism most responsible for acute urinary tract infections, was not the only or even the main offending pathogen in this more-chronic condition. Antibiotic protection assays with shed patient cells and in vitro infection studies using patient-derived strains in cell culture suggested that LUTS-associated bacteria are within or extremely closely associated with shed epithelial cells, which explains how routine cultures might fail to detect them. These data have strong implications for the need to rethink our common diagnoses and treatments of chronic urinary tract symptoms.

A randomized controlled trial comparing the efficacy of controlled-release oxybutynin tablets (10 mg once daily) with conventional oxybutynin tablets (5 mg twice daily) in patients whose symptoms were stabilized on 5 mg twice daily of oxybutynin

Objective To compare the efficacy of a controlled‐release (CR) formulation of oxybutynin with that of conventional oxybutynin in patients with detrusor instability or detrusor hyper‐reflexia whose symptoms were stabilized on conventional oral oxybutynin tablets.

The Inadequacy of Urinary Dipstick and Microscopy as Surrogate Markers of Urinary Tract Infection in Urological Outpatients With Lower Urinary Tract Symptoms Without Acute Frequency and Dysuria

PURPOSE Diagnosing urinary infection in patients with chronic lower urinary tract symptoms without dysuria is a critical step. In this study we scrutinize the sensitivity and specificity of dipstick urinalysis and microscopic pyuria (10 or more white blood cells per microl) to identify infection in such patients. MATERIALS AND METHODS This was a prospective, blinded, observational cohort study of urological outpatients with painless lower urinary tract symptoms. Midstream and catheter urine samples were analyzed. A total of 508 midstream urine samples were used to compare leukocyte esterase, nitrite dipstick and urine microscopy with cultures seeking 10(5) cfu/ml. Similarly 470 catheter urine samples were used to compare the same surrogates with 10(5) cfu/ml and with an enhanced culture method seeking 10(2) cfu/ml. A comparison of leukocyte esterase against microscopic pyuria was made using the 508 midstream and 470 catheter specimens of urine. Midstream urine specimens were provided by 42 normal volunteers for comparison. RESULTS For a midstream urine culture at 10(5) cfu/ml leukocyte esterase was 56% sensitive, nitrite was 10% sensitive and microscopic pyuria was 56% sensitive. Specificities were 66%, 99% and 72%, respectively. For a catheter specimen of urine culture at 10(5) cfu/ml leukocyte esterase was 59% sensitive, nitrite was 20% sensitive and microscopic pyuria was 66% sensitive. Specificities were 84%, 97% and 73%, respectively. The enhanced culture of catheter specimen of urine at 10(2) cfu/ml was positive in 29% of patients vs 15% at 10(5) cfu/ml. CONCLUSIONS Despite official guidelines and widespread use these tests cannot be considered appropriate for diagnosing urinary tract infection in patients with lower urinary tract symptoms, and should be abandoned in this context.

Age-associated changes in detrusor sensory function in women with lower urinary tract symptoms.

This study examined changes in bladder sensation which occur with age in women. 1381 women (age range 20–95 years, mean 54.9) with symptoms of lower urinary tract dysfunction underwent urodynamic study. The bladder capacity at which they first became aware of the desire to void was taken as a quantitative measure of bladder sensation. Maximum bladder capacity fell in the eighth and ninth decades (H=95.84, df=7,P=0.00), but by contrast bladder capacity at first desire to void rose progressively in association with age, both in the group as a whole (H=17.13, df=7,P=0.017) and in a subgroup with detrusor instability (n=952, H=15.42, df=7,P=0.032). This rise in capacity points to a decrease in bladder sensation in association with age. This is not due to neurological disease, antimuscarinic drugs or oestrogens, as the median capacity at first desire to void of these three subgroups did not differ significantly from that of the group as a whole.

A Urodynamic Analysis of Age Associated Changes in Urethral Function in Women with Lower Urinary Tract Symptoms

PURPOSE The urethral resistance relation was studied in relation to stress incontinence and detrusor instability, and used to examine age related differences in women. MATERIALS AND METHODS We investigated women with lower urinary tract symptoms and analyzed pressure-flow plot data. RESULTS Women with pure detrusor instability had greater detrusor pressures at urethral opening and closure than those with a stable bladder and no stress incontinence. The latter women had greater detrusor opening and closing pressures than those with a stable bladder and genuine stress incontinence at all ages. Detrusor pressures at urethral opening and closure were less in absolute terms in association with greater age. Urethral resistance was lower during voiding in women with stress incontinence. CONCLUSIONS Our analysis showed a distinct difference in detrusor pressures at urethral opening and closure between women with and without stress incontinence. Differences were also demonstrated between women with and without detrusor instability. We found lower values of these indirect measures of urethral function in association with greater age. There was no evidence of lower urethral compliance in older women with lower urinary tract symptoms.

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.

Coated catheters for intermittent catheterization: smooth or sticky?

Objective To evaluate the current range of hydrophilic‐coated catheters for intermittent self‐catheterization, focusing on the adherence of the catheter to the urethral mucosa at the end of catheterization.

Discrediting microscopic pyuria and leucocyte esterase as diagnostic surrogates for infection in patients with lower urinary tract symptoms: Results from a clinical and laboratory evaluation

Microscopic pyuria is widely used as a surrogate marker of infection, although there is little data supporting its use in patients who present with non‐acute LUTS. The effects of urinary storage, preservation, and the use of laboratory methods to enhance leucocyte detection, are also unclear. This large, prospective study highlights the poor performance of dipstick urine analysis, and direct microscopy, as surrogate markers of UTI in patients with LUTS. A series of laboratory analyses also examine the effects of urine handling and processing on test integrity, which have important implications for clinical practice.

Measurement of skin elasticity on the foot

Background/purpose: The Cutometer® 580 MPA is a device that is designed to measure the viscoelastic properties of skin in response to the application of negative pressure. The aim of this study was to test the Cutometer® 580 MPA for the repeatable, quantitative measurement of the specific indices of elasticity of pedal skin. The device was used to measure and compare these indices at weight‐bearing and non‐weight‐bearing skin sites on the foot.

Enterococcus faecalis subverts and invades the host urothelium in patients with chronic urinary tract infection.

Bacterial urinary tract infections (UTI) are a major growing concern worldwide. Uropathogenic Escherichia coli has been shown to invade the urothelium during acute UTI in mice and humans, forming intracellular reservoirs that can evade antibiotics and the immune response, allowing recurrence at a later date. Other bacterial species, such as Staphylococcus saprophyticus, Klebsiella pneumonia and Salmonella enterica have also been shown to be invasive in acute UTI. However, the role of intracellular infection in chronic UTI causing more subtle lower urinary tract symptoms (LUTS), a particular problem in the elderly population, is poorly understood. Moreover, the species of bacteria involved remains largely unknown. A previous study of a large cohort of non-acute LUTS patients found that Enterococcus faecalis was frequently found in urine specimens. E. faecalis accounts for a significant proportion of chronic bladder infections worldwide, although the invasive lifestyle of this uropathogen has yet to be reported. Here, we wanted to explore this question in more detail. We harvested urothelial cells shed in response to inflammation and, using advanced imaging techniques, inspected them for signs of bacterial pathology and invasion. We found strong evidence of intracellular E. faecalis harboured within urothelial cells shed from the bladder of LUTS patients. Furthermore, using a culture model system, these patient-isolated strains of E. faecalis were able to invade a transitional carcinoma cell line. In contrast, we found no evidence of cellular invasion by E. coli in the patient cells or the culture model system. Our data show that E. faecalis is highly competent to invade in this context; therefore, these results have implications for both the diagnosis and treatment of chronic LUTS.