Vikram Khullar

Localization of M2 and M3 Muscarinic Receptors in Human Bladder Disorders and Their Clinical Correlations

PURPOSE We studied the cellular localization of muscarinic receptor subtypes 2 and 3 in the human bladder and related any changes in overactive and painful bladder syndromes to measures of clinical dysfunction. MATERIALS AND METHODS Bladder specimens obtained from patients with painful bladder syndrome (11), idiopathic detrusor overactivity (12) and from controls with asymptomatic microscopic hematuria (16) were immunostained using specific antibodies to muscarinic receptor subtypes 2 and 3, and to vimentin, which is a marker for myofibroblasts. Immunostaining results were quantified with computerized image analysis and correlated with clinical dysfunction using frequency and urgency scores. RESULTS Muscarinic receptor subtype 2 and 3 immunoreactivity was observed in the urothelium, nerve fibers and detrusor layers. In addition, strong myofibroblast-like cell staining, similar to vimentin, was present in the suburothelial region and detrusor muscle. A significant increase in suburothelial myofibroblast-like muscarinic receptor subtype 2 immunoreactivity was seen in patients with painful bladder syndrome (p = 0.0062) and idiopathic detrusor overactivity (p = 0.0002), and in muscarinic receptor subtype 3 immunoreactivity in those with idiopathic detrusor overactivity (p = 0.0122) with a trend in painful bladder syndrome. Muscarinic receptor subtype 2 and 3 immunoreactivity significantly correlated with the urgency score (p = 0.0002 and 0.0206, respectively) and muscarinic receptor subtype 2 immunoreactivity correlated with the frequency score (p = 0.0029). No significant difference was seen in urothelial and detrusor muscarinic receptor subtypes 2 and 3 or vimentin immunostaining. CONCLUSIONS To our knowledge this is the first study to show the cellular localization of muscarinic receptor subtypes 2 and 3 in the human bladder. The increase in muscarinic receptor subtypes 2 and 3 immunostaining in myofibroblast-like cells in clinical bladder syndromes and its correlation with clinical scores suggests a potential role in pathophysiological mechanisms and the therapeutic effect of anti-muscarinic agents.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies.

To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.

Can ultrasound replace ambulatory urodynamics when investigating women with irritative urinary symptoms

Objective To determine whether transvaginal ultrasound measurement of bladder wall thickness could replace ambulatory urodynamics when investigating women with lower urinary tract dysfunction not explained by conventional laboratory urodynamic studies.

Direct imaging of the pelvic floor muscles using two‐dimensional ultrasound: a comparison of women with urogenital prolapse versus controls

Objective  To evaluate the anatomy of the levator ani muscle in women with urogenital prolapse versus matched controls without prolapse using real‐time two‐dimensional (2‐D) ultrasound.

Comparison of the efficacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome

This publication follows an abstract submitted by Khullar et al. to the ICS Meeting 2004. The article contains essentially the same data only published now with the prominent names of Abrams, Cardozo, Chapple – and thus weighted with significant authority – so that a closer view is indicated. Unfortunately, comparison of this full paper with the short abstract shows that the chances for greater clarity are missed and numerous significant aspects are now even less clear. It is stated that ‘patients with a clinical diagnosis of idiopathic OAB with detrusor overactivity (DO)’ have been included , which sounds as if DO is used here as a diagnosis, although the ICS clearly defines DO just as an urodynamic observation. But then the DO observed during urodynamics is called involuntary detrusor contraction (IDC). Also, using the ICS definition for suspected prostatic bladder outlet obstruction on females is misleading. Unfortunately, the urodynamic methodology receives minimal description. Only the abstract mentions that micro-tip transducers are used in the rectum for recording abdominal pressure, a method with the relatively highest incidence of artifacts. Further, the very important aspects of data quality control are only vaguely mentioned although not specified. A ‘validated Gaeltec software’ has been used to determine key parameters, but no reference is given and I do not think there is any such software objectively validated , for example, by the ICS. There are too many problems in this publication for a comprehensive discussion. Thus, I will concentrate on the key parameters seemingly showing some statistically significant differences, that is, the number and duration of involuntary contraction with and without symptoms. Data is missing on how many patients had IDC at any time, while it is well known that it is found in 69% of healthy asymptomatic. Because of this high incidence, it has been concluded that such activity may represent a variation of normal, and ‘it can be seen that the (IDC), will vary considerably depending on the criteria applied and thus is likely to be the least useful marker of detrusor activity’. No criteria or definitions of any parameter is specified here. Complex criteria have been suggested to overcome these severe limitations and make ambulatory urodynamic monitoring useful, even by one co-author (CC), however, none of these criteria have been applied or discussed critically. Most disturbing here is that the placebo effect is completely ignored. Only the read-by-title abstract mentions that ‘. . . there was also evidence of a strong placebo effect . . .’ and that treatment comparison to placebo did not reach significance. This is clearly confirmed by Figure 1b where placebo shows the lowest normalized score of symptomatic contractions after treatment, identical to oxybutynin. It can be deduced from the figures that no statistically significant differences to placebo exist, but this information is missing in the text. In summary, it is very discouraging that with ambulatory urodynamics a seemingly advanced methodology is used with the original claim to be more sensitive, but the most impressive result is the strong placebo effect. This mainly confirms that any such uncritical use of ambulatory urodynamics is doubtful and unlikely to identify any drug effect. Nevertheless, the claim is made that this study shows one drug to be more effective than another drug. This publication does not support any such specific claim, and clearly does not confirm the general conclusion that such ambulatory urodynamics ‘may therefore be the most sensitive technique for assessing the therapeutic efficacy of pharmacologically active agents such as antimuscarinics’.

Comparison of the efficacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome: Comparison of properine and oxybutynin

Aim:  To compare the effects of propiverine and oxybutynin on ambulatory urodynamic monitoring (AUM) parameters, safety, and tolerability in patients with overactive bladder.

The relationship between urinary symptom questionnaires and urodynamic diagnoses: an analysis of two methods of questionnaire administration

Objective  To assess whether method of administration of a standard urinary symptom questionnaire alters the relationship of symptoms with urodynamic diagnoses.

Urogynaecological problems in pregnancy and postpartum sequelae.

Purpose of review Women in pregnancy can experience lower urinary tract symptoms which are related to the pregnancy and delivery and iatrogenic, and related to use of epidural anaesthesia and urethral catheters. This article assesses the controversial relationship between pregnancy and delivery and the development of urinary incontinence and pelvic organ prolapse. Recent findings Lower urinary tract symptoms are common in pregnancy and they peak in the third trimester. If women have lower urinary tract symptoms prior to pregnancy, they are more likely to persist after delivery. Vaginal delivery is the factor most strongly associated with stress urinary incontinence after delivery and elective caesarean section may be protective. Vaginal childbirth causes levator ani injury and increase in levator hiatus size, and these persist following vaginal delivery. Women with levator ani injuries may be twice as likely to develop uterovaginal prolapse. Voiding difficulties are more likely to occur after a traditional epidural than a low dose or combined spinal epidural. Summary There is radiological evidence supporting pelvic floor injury following vaginal childbirth and epidemiological evidence for the relationship between vaginal delivery and urinary incontinence and pelvic organ prolapse. Rigorous long-term studies are needed to identify the direct relationship between these two phenomena.

A cost-effectiveness analysis of delayed sphincteroplasty for anal sphincter injury.

Objective  Anal‐sphincter injury may result in faecal incontinence. Sphincteroplasty is usually performed as a primary (immediate) procedure. Delayed sphincteroplasty (DS) can be performed if there is significant trauma or soiling, if the primary procedure has failed, and if the injury was not recognized initially. This study aimed to determine the cost to patient and health service in the event a DS is performed.

Validation study of the Self‐Assessment Goal Achievement (SAGA) questionnaire for lower urinary tract symptoms

Background: Patients’ treatment goals for overactive bladder (OAB) and other lower urinary tract symptoms (LUTS) may not be aligned with their healthcare provider’s goals. Successful management of OAB symptoms is improved by individualised treatment plans with attainable treatment goals. Goal attainment setting may facilitate patient–provider interaction and the development of a personalised treatment plan based on realistic, individual goals, thereby increasing patient satisfaction and therapeutic outcomes. The purpose of this study was to validate the utility of the Self‐Assessment Goal Achievement (SAGA) questionnaire for LUTS in helping patients identify and achieve realistic treatment goals.