Jeremy G. Noble

STUDIES OF THE PATHOPHYSIOLOGY OF IDIOPATHIC DETRUSOR INSTABILITY: THE PHYSIOLOGICAL PROPERTIES OF THE DETRUSOR SMOOTH MUSCLE AND ITS PATTERN OF INNERVATION

PURPOSE Idiopathic detrusor instability (IDI) is a common cause of lower urinary tract storage symptoms, such as urgency, frequency and urge incontinence. We have investigated the in vitro properties and pattern of innervation of the detrusor from patients with this condition. MATERIALS AND METHODS Full thickness bladder specimens were obtained perioperatively from 14 patients with IDI and from 14 cadaveric controls undergoing transplant organ retrieval. Isolated detrusor smooth muscle strips were mounted in organ baths for isometric tension recording. Frequency-response curves to electrical field stimulation (EFS) (1 Hz to 50 Hz) and concentration response curves for carbachol (10(-7) M to 5 x 10(-4) M) and potassium (12 mM to 120 mM) were constructed. Acetylcholinesterase histochemistry and immunohistochemistry for both phosphorylated and non-phosphorylated neurofilaments was carried out on frozen sections of control and IDI bladders. RESULTS IDI strips developed greater spontaneous tone (0.25 gm./mg. versus 0.12 gm./mg.; p <0.0001) and more spontaneous fused tetanic contractions (16.8% versus 6.8%; p <0.005) during an initial 90 minutes equilibration period. The IDI strips were less responsive than controls to nerve stimulation (max. response to EFS 0.79 gm./mg. versus 1.23 gm./mg.; p <0.0001) and were supersensitive to potassium (EC50 39.7 mM versus 45.7 mM; p = 0.003) but not to carbachol (EC50 7.3 x 10(-6) M versus 6.6 x 10(-6) M; p = 0.48). Morphometric studies revealed reduced staining of presumed cholinergic nerves, with 34.7% of IDI smooth muscle bundles appearing denervated compared with 1.5% of controls (p <0.0001). CONCLUSIONS Our study supports the notion that there is a fundamental abnormality in IDI at the level of the bladder wall, with evidence of altered spontaneous contractile activity consistent with an increased electrical coupling of cells, a patchy denervation of the detrusor and a potassium supersensitivity.

Trends in urological stone disease

Study Type – Therapy (case series)

Ureteric trauma in gynecologic surgery

Nearly all gynecological procedures have been reported to cause ureteric injury, with an incidence of 0.4%–2.5% for non-malignant conditions. The incidence is rising as more ambitious operations are undertaken laparoscopically. Risk factors for ureteric injury include cancer, hemorrhage, endometriosis, adhesions and an enlarged uterus. Tyes of injury include ligation, crush, laceration, avulsion, stretch and devascularization. The diagnosis may be obvious intraoperatively, but postoperative presentation with loin pain, pyrexia, fistula or non-specific signs is more common. A significant number are asymptomatic. Early diagnosis is vital, and urological investigation should be considered in any patient who is not recovering as expected. Injuries recognized intraoperatively should be repaired during the same operation. Delayed recognized injuries are being managed conservatively with increasing success in selected cases. Early operative repair achieves good results unless the injury is severe. Litigation is less likely if the diagnosis is prompt, repair is successful and the patient is treated with consideration.

NITRIC OXIDE SYNTHASE IN THE HETEROGENEOUS POPULATION OF INTRAMURAL STRIATED MUSCLE FIBRES OF THE HUMAN MEMBRANOUS URETHRAL SPHINCTER

PURPOSE Nitric oxide (NO) is known to relax urethral smooth muscle. The role of NO in the control of urethral striated muscle remains unknown. We have investigated the distribution of nitric oxide synthase (NOS) immunoreactivity and its possible relationship with subtypes of intramural striated muscle fibers in the human male membranous urethra. MATERIALS AND METHODS Whole transverse cryostat sections from seven membranous urethrae were studied using NOS immunohistochemistry and NADPH diaphorase histochemistry. Striated fiber subtypes were demonstrated using immunohistochemistry for troponin T and histochemistry for myofibrillary adenosine triphosphatase (ATPase). Consecutive sections were used to assess the correlation between the distribution of NOS immunoreactivity and the type of striated fibers. RESULTS NOS immunoreactivity and NADPH diaphorase activity were detected in the sarcolemma of 48.5% of the intramural striated muscle fibers. NOS immunoreactive nerve trunks and fine nerve fibers, a few of which appeared to end on muscle fibers, were present in the striated sphincter. Fast twitch fibers were detected by ATPase staining, and also exhibited positive immunoreactivity for troponin T, constituting 34.6% of the total number of striated fibers. Two populations of slow twitch fibers were identified; one with small diameter (mean: 15.7 microns) and another of larger diameter (mean: 21.7 microns) comparable to that of fast twitch fibers. 86% of the fast twitch fibers and 29% of slow twitch fibers (most of which had larger diameters) exhibited NOS immunoreactivity and NADPH diaphorase activity in the sarcolemma. CONCLUSIONS The presence of nitrergic nerve fibers in the striated urethral sphincter suggests an involvement in the innervation of urethral striated muscle. Furthermore, the presence of NOS immunoreactivity in the sarcolemma may indicate a role for NO in the regulation of urethral striated muscle metabolism and contraction.

RADIOTELEMETERED CYSTOMETRY IN PIGS: VALIDATION AND COMPARISON OF NATURAL FILLING VERSUS DIURESIS CYSTOMETRY

PURPOSE Cystometry has previously been performed in awake animals using vesical and abdominal catheters, and artificial bladder filling. Conventional urodynamic recordings may be obtained in this manner, albeit under nonphysiological and potentially stressful conditions. Therefore, we developed a technique to perform continuous, ambulatory cystometric monitoring in pigs. MATERIALS AND METHODS A dual pressure radiotelemetry device was surgically implanted in 22 large white pigs. Vesical and abdominal pressures were recorded and validated, subtracted detrusor pressures were derived and natural fill and diuresis cystometry was compared. RESULTS Continuous recordings were obtained for 1 to 24 hours, and the devices remained in the animals for up to 3 months. There were few complications and incrustation of the intravesical catheter tip occurred but it did not appear to affect recorded pressures. The pressure data were validated by comparison with filling pressures during bladder distention and simultaneous conventional cystometry at the end of the experimental period. Comparison of natural filling and diuresis cystometrograms showed that natural bladder filling results in higher maximum detrusor pressure during voiding (38.1 versus 33.9 cm. H2O, p <0.05), higher detrusor pressure after contractions (42.6 versus 32.2 cm. H2O, p <0.05) and more frequent detection of unstable contractions in pigs with detrusor instability secondary to experimental manipulation of the lower urinary tract (77.8% versus 45.0%, p <0.05). CONCLUSIONS This technique allows continuous cystometric monitoring in less stressed animals under more physiological conditions for relatively long periods and, thus, allows prolonged assessment of bladder function in pigs in response to pathological and pharmacological manipulations. Nonphysiological rates of bladder filling have been shown to result in detrusor inhibition, which emphasizes the importance of ambulatory cystometry when describing bladder function.

Label-free quantitative proteomics reveals differentially regulated proteins influencing urolithiasis

Urinary proteins have been implicated as inhibitors of kidney stone formation (urolithiasis). As a proximal fluid, prefiltered by the kidneys, urine is an attractive biofluid for proteomic analysis in urologic conditions. However, it is necessary to correct for variations in urinary concentration. In our study, individual urine samples were normalized for this variation by using a total protein to creatinine ratio. Pooled urine samples were compared in two independent experiments. Differences between the urinary proteome of stone formers and nonstone-forming controls were characterized and quantified using label-free nano-ultraperformance liquid chromatography high/low collision energy switching analysis. There were 1063 proteins identified, of which 367 were unique to the stone former groups, 408 proteins were unique to the control pools, and 288 proteins were identified for comparative quantification. Proteins found to be unique in stone-formers were involved in carbohydrate metabolism pathways and associated with disease states. Thirty-four proteins demonstrated a consistent >twofold change between stone formers and controls. For ceruloplasmin, one of the proteins was shown to be more than twofold up-regulated in the stone-former pools, this observation was validated in individuals by enzyme-linked immunosorbent assay. Moreover, in vitro crystallization assays demonstrated ceruloplasmin had a dose-dependent increase on calcium oxalate crystal formation. Taken together, these results may suggest a functional role for ceruloplasmin in urolithiasis.

The contribution of cholinergic detrusor excitation in a pig model of bladder hypocompliance

Objective To investigate the role of cholinergic excitation in mediating changes in detrusor compliance (manifested on conventional cystometry as an incremental rise in detrusor pressure as bladder volume increases) under conditions of propofol‐sedation in the pig.

Flexible cystoscopy findings in patients investigated for profound lower urinary tract symptoms, recurrent urinary tract infection, and pain.

BACKGROUND AND PURPOSE The National Institute of Clinical Excellence published guidelines in 2010 recommending the use of cystoscopy to investigate profound lower urinary tract symptoms (pLUTS), recurrent urinary tract infection (rUTI), and pain in men. Currently, there are no equivalent guidelines for women. We aimed to examine the diagnostic performance of flexible cystoscopy (FC) when it is used in this context in both men and women. PATIENTS AND METHODS Results of all outpatient FCs undertaken in our department between April 2009 and March 2010 were examined retrospectively. Patients undergoing FC for the investigation of pLUTS, rUTI, or pain were included. Diagnostic performance was calculated, which was defined as the number of patients receiving a diagnosis of a clinically relevant abnormality at FC divided by the total number of patients undergoing FC for this indication. RESULTS Of the 1809 patients who underwent FC during the study period, 113 underwent FC to investigate pLUTS, rUTI, or pain. Diagnostic performance was 11.5% (n=13), being 11.4%, 19.2%, and 0% in those with pLUTS, rUTI, and pain, respectively. Bladder cancer was diagnosed in one (0.9%) patient who underwent FC to investigate pLUTS but also had nonvisible hematuria. Urethral stricture was diagnosed in nine (8.0%) cases and intravesical calculi in four (3.5%) cases. CONCLUSION Clinically relevant abnormalities were found in 11.5% of patients with pLUTS, rUTI, or pain, supporting recently published NICE guidelines recommending cystoscopy in patients with pLUTS or rUTI. Of the 17 patients who were investigated for pain, none was found to have clinically relevant abnormalities; further studies are needed to define the clinical utility of FC in these cases.

Caudal clonidine-bupivicaine block with bladder hydrodistension: a novel combined treatment for the painful bladder.

The authors describe a new combination procedure consisting of bladder hydrodistension with clonidine-bupivicaine caudal block for the symptomatic relief of bladder pain. They report this new technique whereby patients who had tried multiple forms of therapy with little response, including bladder hydrodistension under general anaesthesia for their chronic pelvic bladder pain, responded to this novel combination therapy.

Dysuria and a headache

A 49-year-old white woman was referred to us in March, 2003, with symptoms of recurrent urinary tract infections. She had no other medical history of note, and had not travelled outside of the UK. Her general practitioner reported that the urine dipsticks repeatedly detected leucocytes, but ad hoc cultures showed no growth. Early morning cultures were not done. We did an intravenous urography and ultrasound and found no abnormalities. Cystoscopy showed an inflamed bladder that bled on distension, and we sent biopsy samples for analysis; these were reported as showing “cystitis, not otherwise specified”. We made a diagnosis of interstitial cystitis, and several months later, the patient developed urge incontinence requiring intermittent self