A conversation on how animal experimental studies allies with translational medicine.

Basis science research in pediatric urology studies physiological questions in animal models to provide new data on how to treat patients. We sat down with Jens-Christian Djurhuus to discuss both practical and philosophical questions on how to best perform basic science research. Initial questions such as "What type of questions are best studied in animal models?" and "Which animal model should I use?" help us answer the basic question of "What is a good research topic?". To take advantage of his experience leading a research team, we went on to discuss "How do you lead a research team?" and "How do we make sure that basic science research translates to clinical practice?". As research funding becomes scarce, we thank Professor Djurhuus for his insights on how to focus basic science research on relevant topics that are easily translatable to the care of children.

Gender-dependent bladder response to one-day bladder outlet obstruction.

BACKGROUND: Development of bladder fibrosis, loss of compliance, and voiding dysfunction are among the severe consequences of various lower urinary conditions, for example, bladder outlet obstruction (BOO), neurogenic bladder, and radiotherapy to the pelvic area. The bladder remodelling results in significant changes in bladder function and architecture, and may ultimately be deleterious for kidney function. The molecular signals underlying pathologic bladder remodelling, as well as the impact of gender, remain poorly understood. OBJECTIVE: To investigate the bladder remodelling after one day BOO, whether the remodelling is different between different bladder sections, and whether genders may affect the remodelling. STUDY DESIGN: Thirty male and 30 female C57BL/6NRj mice were randomly divided into Control, Sham and BOO groups with ten mice per group. A 24-h total urethral obstruction was performed at the proximal urethra. Histological changes were observed via H&E, trichrome and immunohistochemistry staining. Harvested bladders were divided into upper and lower sections for analysis. Protein and gene expression were detected by Western blotting and qPCR. RESULTS: No significant changes in bladder wall thickness were observed following BOO, while increased bladder mass after BOO was found in female mice only. We detected FN and ⍺-SMA upregulation in the male upper bladder segment. Female BOO mice bladders showed increased α-SMA expression in both bladder segments, but no difference of FN was observed in either bladder segments. BOO-induced upregulation of TGF-ß and Gremlin were detected in both male and female bladders, while downregulation of BMP-7 was detected only in male bladders. Furthermore, phosphorylation of both SMAD2/3 and SMAD1/5/9 were increased in male bladders following BOO, whereas female mice exhibited increased pSMAD2/3 in the upper and increased pSMAD1/5/9 in the lower bladder segment. CONCLUSIONS: Our data indicate that some specific proteins and growth factors were detected as early alterations of tissue which may lead to fibrosis. In addition, the males tended to have more pronounced response than females. However, the causes and consequences of the findings need to be further investigated.

[Introduction on how to write a scientific abstract].

In this review, a guide on how to write a scientific abstract is given. When junior researchers submit an abstract for a conference or a manuscript for a journal, a well-written abstract is the key to acceptance and publication. Being able to catch the interest of the reader, while keeping the length to a minimum, is an art, which can be learned by practice.

International Continence Society (ICS) report on the terminology for nocturia and nocturnal lower urinary tract function.

INTRODUCTION: The terminology for nocturia and nocturnal lower urinary tract function is reviewed and updated in a clinically and practically-based consensus report. METHODS: This report has been created by a Working Group under the auspices and guidelines of the International Continence Society (ICS) Standardisation Steering Committee (SSC). All relevant definitions were updated on the basis of research over the last 16 years since the publication of the first nocturia standardization document in 2002. An extensive process of 16 rounds of internal and external reviews was involved to examine each definition exhaustively, with decision-making by collective opinion (consensus). RESULTS: A clinically-based terminology report for nocturia and nocturnal lower urinary tract function, encompassing five key definitions divided into signs and symptoms has been developed. Clarity and user-friendliness have been key aims to make it interpretable by healthcare professionals and allied healthcare practitioners involved in the care of individuals with nocturnal lower urinary tract function. CONCLUSION: A consensus-based terminology report for nocturia and nocturnal lower urinary tract function has been produced to aid clinical practice and research.

ICS educational module: Cystometry in children.

AIMS: To introduce the standard procedure of cystometry and interpretation of the results in children. METHODS: The literature on cystometry in children in PubMed for the last 20 years was reviewed. The updated knowledge regarding indication, preparation, technique, and interpretation of cystometry in children were summarized. RESULTS: Filling cystometry is the core content of a paediatric urodynamic study. In this section, the technique for performing cystometry is introduced in details. Emphasis is placed on correctly setting up the equipment according to ICS and ICCS guidelines, using appropriate terminology, providing indications for its performance with specific considerations for children, and proper interpretation of results. CONCLUSIONS: Cystometry can be used in children including newborn to evaluate lower urinary tract dysfunction.

Long-term urodynamic findings following radical prostatectomy and salvage radiotherapy.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are common following radical prostatectomy (RP) or intended curative radiotherapy in prostate cancer patients. One-quarter of those treated with RP experience biochemical failure and are subsequently offered salvage radiotherapy (SRT) to the prostatic bed. The aim of this study was to elucidate long-term LUTS after surgery and SRT. MATERIALS AND METHODS: Urodynamic parameters from 16 patients treated with RP and subsequent SRT in the period 2000-2010 were evaluated with uroflowmetry, filling cystometry, pressure-flow and urethral pressure profile (UPP). In conjunction with the urodynamic examination, all patients completed the Danish Prostatic Symptom Score (DAN-PSS) questionnaire, which evaluates the grade of LUTS. RESULTS: Median time from SRT to urodynamic examination was 7.7 years (range 5.8-10.0 years). The following urodynamic parameters were affected: bladder volume at maximal cystometric capacity, bladder compliance, bladder function, bladder outlet obstruction and UPP. The total DAN-PSS index combining all symptoms and their corresponding impact on patients was mild in six patients (≤ 7 points), moderate in seven patients (8-19 points) and severe in three patients (≥ 20 points). CONCLUSIONS: This urodynamic study is one of the first to evaluate long-term urodynamic characteristics in patients treated with SRT. Several urodynamic parameters were affected. This indicates that SRT primarily affects bladder compliance, maximal cystometric capacity and bladder outlet obstruction. LUTS were proven to be strongly related to urodynamic parameters.

Evaluation of Hospital-Based Hematuria Diagnosis and Subsequent Cancer Risk Among Adults in Denmark.

Importance: Data on the long-term risk of urologic and nonurologic cancer after hematuria diagnosis are sparse. Such data can improve understanding of hematuria and cancer and can provide insight into the clinical course of patients with hematuria. Objective: To assess the risk of urologic or nonurologic cancer after a hospital-based diagnosis of hematuria. Design, Setting, and Participants: This cohort study used population-based, nationwide health care databases covering all hospitals in Denmark. The data set included records of all adults (n = 134 173) with an inpatient, outpatient, or emergency department diagnosis of hematuria. The study was conducted from January 1, 1995, to December 31, 2013. Follow-up ended on December 31, 2013. Data analysis was performed from January 16, 2017, to September 18, 2018. Main Outcomes and Measures: Cumulative risk of cancer was computed, and observed cancer incidence was compared with incidence expected in the general population, using standardized incidence ratios. Results: Of the 134 173 patients included, 52 367 (39.0%) were women, 81 806 (61.0%) were men, and the median (interquartile range) age was 59 (44-72) years. Within 3 months after hematuria diagnosis, 2647 patients (1.9%) received an invasive bladder cancer diagnosis, 1077 (0.8%) a noninvasive bladder cancer diagnosis, 569 (0.4%) a kidney cancer diagnosis, and 908 (1.1%) a prostate cancer diagnosis. The 3-month cumulative incidence (or absolute risk) of any cancer diagnosis was 4.81% (95% CI, 4.70%-4.93%), the 1-year risk was 6.65% (95% CI, 6.51%-6.78%), and the 5-year risk was 12.34% (95% CI, 12.15%-12.53%). The cumulative incidence of bladder cancer only increased from 1.20% (95% CI, 1.11%-1.30%) after 1 year to 1.36% (95% CI, 1.26%-1.46%) after 5 years of follow-up in women and from 2.93% (95% CI, 2.82%-3.05%) to 3.31% (95% CI, 3.19%-3.44%) in men. For noninvasive bladder cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 5.39 (95% CI, 4.58-6.30) in patients without initial cystoscopy and was 0.16 (95% CI, 0.04-0.42) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. For kidney cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 2.63 (95% CI, 2.15-3.18) in patients without cystoscopy and 1.20 (95% CI, 0.87-1.61) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. After 1 year, the risk of gynecologic and colorectal cancers was as expected or even lower, whereas the risk of hematologic malignant neoplasms remained slightly elevated. Conclusions and Relevance: Increased risk of bladder and kidney cancers even more than 1 year after hospital-based hematuria diagnosis, as well as the slightly elevated risk of invasive bladder cancer after 5 years, may indicate that it is a marker of greater cancer risk; these findings could inform follow-up recommendations for hematuria.

Oral Contraceptives and Renal Water Handling: A diurnal study in young women.

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

Can bladder fibrosis in congenital urinary tract obstruction be reversed?

A variety of conditions exists in adults and children in which functional or anatomical urinary tract obstructions cause bladder fibrosis, which reduces the bladder's ability to store and empty urine. Current surgical procedures include removal of the obstructions to facilitate bladder emptying or prompt prenatal or postnatal spinal closure to prevent further neurogenic damage. Bladder fibrosis may occur, and it can get worse if a flow hindrance persists or deteriorates. Anti-fibrotic therapeutic strategies that target a variety of factors have been developed in animal models, but currently there are no anti-fibrotic therapies available for clinical use. This review examines the pathogenesis of bladder fibrosis that is caused by congenital obstructions of the lower urinary tract, and it focuses on the principal signalling factors and potential treatment modalities.

Adolescents with nocturnal enuresis and daytime urinary incontinence-How can pediatric and adult care be improved-ICI-RS 2015?

AIMS: Nocturnal enuresis (NE) and daytime urinary incontinence (DUI) are common in adolescents. The aim of this paper was to review studies on prevalence, clinical symptoms and associated risk factors and to formulate recommendations for assessment and treatment. MATERIALS AND METHODS: A systematic Scopus search was performed and relevant publications were selected. The topic was discussed during the ICI-RS meeting in 2015. RESULTS: One to two percent of older adolescents are affected by NE and 1% by DUI. NE and DUI are associated with multiple risk factors such as fecal incontinence and constipation, obesity, chronic illness, and psychological impairment. Chronic treatment-resistant, relapsing and new-onset cases can occur. Adolescent NE and DUI can be treated by a multidisciplinary team according to pediatric principles. Additional treatment components have been developed for adolescents. Transition from pediatric to adult services is frequently disorganized. CONCLUSIONS: Incontinence in adolescents is a neglected research topic and clinical care is often suboptimal. As adolescents are seen by both pediatric and adult services, alignment and harmonization of diagnostic and therapeutic principles is needed. Also, an organized transition process is recommended to improve care for adolescent patients. Neurourol. Urodynam. 36:843-849, 2017. © 2017 Wiley Periodicals, Inc.

Is testosterone important in LUT function in men and women? ICI-RS 2015.

AIM: This review article is a collaborative report based upon the Authors' presentations and Group discussion on the role of testosterone (T) in the male and female lower urinary tract (LUT) which took place at the 6th International Consultation on Incontinence Research Society's (ICI-RS) annual meeting, in Bristol, UK (September 8-10, 2015). METHODS: It comprises overviews and opinions on both the current state of knowledge of the role of T in LUT function and dysfunction in both sexes. RESULTS: Results from animal studies suggest that T treatment may be beneficial for disorders of the LUT in women including urinary incontinence and pelvic organ prolapse. The need for clinical studies to evaluate the effect of T treatment in peri- and post-menopausal women, taking into account the type of applied androgen, the application form, timing and dosage, is especially emphasized. In males, findings on the impact of T on the male external urethral sphincter underscores that there is still much to learn about its role in male LUT physiology. The important topic of the use of T therapy in the treatment of enuresis in the young, both sexes, is also discussed. The importance of understanding the steroidogenic pathways linking T with estradiol is discussed as being of paramount importance in researching the unique actions of T in the LUT. CONCLUSION: The overall conclusion is that further research into the role of T in LUT function and dysfunction across genders and age groups (young to old) is extremely important. Neurourol. Urodynam. 36:859-862, 2017. © 2017 Wiley Periodicals, Inc.

No immediate effect on urodynamic parameters during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder and daytime incontinence-A randomized, double-blind, placebo-controlled study.

AIM: To evaluate the immediate effect on natural fill urodynamic parameters and bladder function during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder (OAB) and daytime urinary incontinence (DUI). MEETHODS: In this double-blind, placebo-controlled study, 24 children with severe OAB and DUI (mean age 8.5 ± 1.2 years) underwent 48-h natural fill urodynamics. After 24 h of baseline investigation, the children were randomized to either active continuous TENS (n = 12) or placebo TENS (n = 12) over the sacral S2-S3 outflow. The urodynamic recordings were analyzed manually for three different bladder contraction patterns resulting in a void. The number of bladder contractions not leading to a void was also calculated. Maximum voided volume (MVV) and average voided volume (AVV) were identified for both the baseline and the intervention day. RESULTS: We found that TENS had no immediate objective effect on bladder capacity. The difference (before minus after treatment) in MVV/EBC in the active TENS group = 0.03 ± 0.23 versus placebo TENS group = -0.01 ± 0.10 (P = 0.61). Also, there was no significant difference in the proportion of different bladder contraction types between the two groups. TENS did not significantly influence the number of bladder contractions not leading to a void. Results are presented as mean ± SD. CONCLUSION: There is no immediate objective effect of TENS on bladder activity assessed by natural fill urodynamics in children with OAB and DUI.

Fundamentals and clinical perspective of urethral sphincter instability as a contributing factor in patients with lower urinary tract dysfunction--ICI-RS 2014.

AIMS: Urethral pathophysiology is often neglected in discussions of bladder dysfunction. It has been debated whether "urethral sphincter instability," referred to based on observed "urethral pressure variations," is an important aspect of overactive bladder syndrome (OAB). The purpose of this report is to summarize current urethral pathophysiology evidence and outline directions for future research based on a literature review and discussions during the ICI-RS meeting in Bristol in 2014. METHODS: Urethral pathophysiology with a focus on urethral pressure variation (UPV) was presented and discussed in a multidisciplinary think tank session at the ICI_R meeting in Bristol 2014. This think tank session was based on collaboration between physicians and basic science researchers. RESULTS: Experimental animal studies or studies performed in clinical series (predominantly symptomatic women) provided insights into UPV, but the findings were inconsistent and incomplete. However, UPV is certainly associated with lower urinary tract symptoms (likely OAB), and thus, future research on this topic is relevant. CONCLUSIONS: Future research based on adequately defined clinical (and urodynamic) parameters with precisely defined patient groups might shed better light on the cause of OAB symptoms. Further fundamental investigation of urethral epithelial-neural interactions via the release of mediators should enhance our knowledge and improve the management of patients with OAB.