Pieter Uvin

The influence of malrotation of the femoral component in total knee replacement on the mechanics of patellofemoral contact during gait. An in vitro biomechanical study

Malrotation of the femoral component is a cause of patellofemoral maltracking after total knee arthroplasty. Its precise effect on the patellofemoral mechanics has not been well quantified. We have developed an in vitro method to measure the influence of patellar maltracking on contact. Maltracking was induced by progressively rotating the femoral component either internally or externally. The contact mechanics were analysed using Tekscan. The results showed that excessive malrotation of the femoral component, both internally and externally, had a significant influence on the mechanics of contact. The contact area decreased with progressive maltracking, with a concomitant increase in contact pressure. The amount of contact area that carries more than the yield stress of ultra-high molecular weight polyethylene significantly increases with progressive maltracking. It is likely that the elevated pressures noted in malrotation could cause accelerated and excessive wear of the patellar button.

Functional characterization of a chronic cyclophosphamide‐induced overactive bladder model in mice

To describe a new mouse model of overactive bladder (OAB) at the histological level, pain, voiding behavior, and urodynamics, while assessing the physiological state of mice.

Graft-related complications and biaxial tensiometry following experimental vaginal implantation of flat mesh of variable dimensions

To compare the occurrence of graft‐related complications (GRCs) and biomechanical properties of meshes implanted vaginally and abdominally.

TRP channels in lower urinary tract dysfunction

Lower urinary tract dysfunction (LUTd) represents a major healthcare problem. Although it is mostly not lethal, associated social disturbance, medical costs, loss of productivity and especially diminished quality of life should not be underestimated. Although more than 15% of people suffer from a form of LUTd to some extent, pathophysiology often remains obscure. In the past 20 years, transient receptor potential (TRP) channels have become increasingly important in this field of research. These intriguing ion channels are believed to be the main molecular sensors that generate bladder sensation. Therefore, they are intensely pursued as new drug targets for both curative and symptomatic treatment of different forms of LUTd. TRPV1 was the first of its class to be investigated. Actually, even before this channel was cloned, it had already been targeted in the bladder, with clinical trials of intravesical capsaicin instillations. Several other polymodally gated TRP channels, particularly TRPM8, TRPA1 and TRPV4, also appear to play a prominent role in bladder (patho)physiology. With this review, we provide a brief overview of current knowledge on the role of these TRP channels in LUTd and their potential as molecular targets for treatment.

Bladder dysfunction in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA.

Essential Role of Transient Receptor Potential M8 (TRPM8) in a Model of Acute Cold-induced Urinary Urgency

BACKGROUND Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU. OBJECTIVE To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1. DESIGN, SETTING, AND PARTICIPANTS Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats. INTERVENTIONS An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test. RESULTS AND LIMITATIONS Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients. PATIENT SUMMARY Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans.

The use of cystometry in small rodents: a study of bladder chemosensation.

The lower urinary tract (LUT) functions as a dynamic reservoir that is able to store urine and to efficiently expel it at a convenient time. While storing urine, however, the bladder is exposed for prolonged periods to waste products. By acting as a tight barrier, the epithelial lining of the LUT, the urothelium, avoids re-absorption of harmful substances. Moreover, noxious chemicals stimulate the bladders nociceptive innervation and initiate voiding contractions that expel the bladders contents. Interestingly, the bladders sensitivity to noxious chemicals has been used successfully in clinical practice, by intravesically infusing the TRPV1 agonist capsaicin to treat neurogenic bladder overactivity. This underscores the advantage of viewing the bladder as a chemosensory organ and prompts for further clinical research. However, ethical issues severely limit the possibilities to perform, in human subjects, the invasive measurements that are necessary to unravel the molecular bases of LUT clinical pharmacology. A way to overcome this limitation is the use of several animal models. Here we describe the implementation of cystometry in mice and rats, a technique that allows measuring the intravesical pressure in conditions of controlled bladder perfusion. After laparotomy, a catheter is implanted in the bladder dome and tunneled subcutaneously to the interscapular region. Then the bladder can be filled at a controlled rate, while the urethra is left free for micturition. During the repetitive cycles of filling and voiding, intravesical pressure can be measured via the implanted catheter. As such, the pressure changes can be quantified and analyzed. Moreover, simultaneous measurement of the voided volume allows distinguishing voiding contractions from non-voiding contractions. Importantly, due to the differences in micturition control between rodents and humans, cystometric measurements in these animals have only limited translational value. Nevertheless, they are quite instrumental in the study of bladder pathophysiology and pharmacology in experimental pre-clinical settings. Recent research using this technique has revealed the key role of novel molecular players in the mechano- and chemo-sensory properties of the bladder.

Crucial Role of TRPC1 and TRPC4 in Cystitis-Induced Neuronal Sprouting and Bladder Overactivity

Purpose During cystitis, increased innervation of the bladder by sensory nerves may contribute to bladder overactivity and pain. The mechanisms whereby cystitis leads to hyperinnervation of the bladder are, however, poorly understood. Since TRP channels have been implicated in the guidance of growth cones and survival of neurons, we investigated their involvement in the increases in bladder innervation and bladder activity in rodent models of cystitis. Materials and Methods To induce bladder hyperactivity, we chronically injected cyclophosphamide in rats and mice. All experiments were performed a week later. We used quantitative transcriptional analysis and immunohistochemistry to determine TRP channel expression on retrolabelled bladder sensory neurons. To assess bladder function and referred hyperalgesia, urodynamic analysis, detrusor strip contractility and Von Frey filament experiments were done in wild type and knock-out mice. Results Repeated cyclophosphamide injections induce a specific increase in the expression of TRPC1 and TRPC4 in bladder-innervating sensory neurons and the sprouting of sensory fibers in the bladder mucosa. Interestingly, cyclophosphamide-treated Trpc1/c4−/− mice no longer exhibited increased bladder innervations, and, concomitantly, the development of bladder overactivity was diminished in these mice. We did not observe a difference neither in bladder contraction features of double knock-out animals nor in cyclophosphamide-induced referred pain behavior. Conclusions Collectively, our data suggest that TRPC1 and TRPC4 are involved in the sprouting of sensory neurons following bladder cystitis, which leads to overactive bladder disease.

Ureteral Stents Do Not Cause Bacterial Infections in Children After Ureteral Reimplantation

OBJECTIVES To determine, in a prospective study, the incidence of bacterial colonization and the risk of bacterial infection of indwelling double-J stents in children undergoing ureteral reimplantation. In a balance between the safety and comfort of the child, the need for postoperative stenting of the reimplanted ureters has been discussed. It is unknown whether an indwelling double-J stent after ureteral reimplantation would be a risk factor for postoperative urinary tract infection. METHODS From 2005 to 2010, 209 children (138 girls and 71 boys; median age 3.8 years) with vesicoureteral reflux underwent unilateral or bilateral cross-trigonal ureteral reimplantation (352 ureters). All children received a single dose of gentamicin (2 mg/kg body weight) and a preoperative bladder rinse with 10% polividone-saline solution. A transurethral catheter was also left postoperatively for 2 (unilateral) or 3 (bilateral) days. The ureter was stented with a 8-22 cm multilength catheter. At 3 weeks postoperatively, the ureteral catheters were removed and investigated for bacterial colonization. RESULTS Of the 209 children, 10 (4.8%) developed a urinary tract infection within the first 6 weeks after ureteral reimplantation. Of the remaining 199 children without any symptoms, 13 (6.5%) had a positive urine culture at removal of the catheters. Of the 199 children without any symptoms, 90 (45.2%) had a positive culture of one or more segments of the double-J catheter. CONCLUSIONS Although the colonization rate of ureteral stents in our study was 42.9%, the rate of urinary tract infection during the first 6 weeks after ureteral reimplantation using indwelling ureteral stents was only 4.6%. We have concluded that the clinical significance of bacterial colonization of an indwelling ureteral stent is low, and therefore, ureteral stents can be used safely.

Urodynamic changes in mice with experimental autoimmune encephalomyelitis correlate with neurological impairment.

Neurogenic bladder dysfunction is a major issue in Multiple Sclerosis (MS). High intravesical pressure should be treated early. Available therapies are insufficient and there is need for drug development and investigation of pathogenesis. Experimental Autoimmune Encephalomyelitis (EAE) in rodents is a well validated model to study MS. Previous research has shown that these animals develop urinary symptoms. However, from clinical studies, we know that symptoms do not necessarily reflect changes in bladder pressure. This paper aims to provide a complete overview of urodynamic changes in a model for detrusor overactivity in MS.