Isolated extraordinary daytime urinary frequency of childhood: a case series of 26 children in Switzerland

BACKGROUND: The term 'isolated extraordinary daytime urinary frequency' designates an abnormally increased diurnal frequency of painless urination in a completely toilet-trained child with normal urinalysis. METHODS: We report the history of 26 children (16 boys and 10 girls; aged between 4.1 and 10 years) who were referred to us between 2002 and 2006 and subsequently diagnosed with this condition. RESULTS: Possible psychosocial problems, or recent emotional stressors, were disclosed in the majority of the children: recent (36 months or less) asylum seekers (n = 9), school-related problems (n = 4), parental divorce (n = 2) or death of the mother (n = 1). Possible dietary causes were observed in 9 patients: oxalate-rich beverages (n = 5) and liberal ingestion of 'acidic' juices (n = 4). A diet low in oxalates was recommended when children were consuming large quantities of oxalate-rich beverages; and a diet low in acidic juice was recommended in those liberally ingesting acidic juices. Reassurance and observation were the approach in the remaining cases. The median duration of the symptoms was 5 months. A longer (p < 0.05) duration was noted in children of asylum seekers. CONCLUSIONS: This functional condition is easily identifiable, but often under- or misdiagnosed. Confounding the condition might result in redundant investigation.

Childhood extraordinary daytime urinary frequency-a case series and a systematic literature review

Childhood extraordinary daytime urinary frequency is likely a common but underreported condition characterized by daytime frequent voiding and typically not linked with complaints of burning, urinary incontinence, altered urinary stream, changes in the nighttime voiding pattern, excessive fluid intake and excessive urinary volume. To determine the features and outcome of extraordinary daytime urinary frequency, we report our experience with 14 children and the results of a formal systematic analysis of peer-reviewed English-language literature on this topic. Nineteen case series were found (together with 16 mostly pertinent comments), with each case series providing details on from one to 119 children. On the basis of our experience and the findings of our systematic analysis, we conclude that, in general practice, extraordinary daytime urinary frequency is a common cause of urinary frequency, that the age of such patients is, on average, 6 years and that the micturation abnormalities persist for an average of 6 months. The results of this review must be viewed with an understanding of the limitations of the analysis process, which incorporated data exclusively from case series.

Does successful treatment of constipation or faecal impaction resolve lower urinary tract symptoms? A structured review of the literature

Consensus guidelines advocate the treatment of constipation and faecal impaction in order to improve symptoms of urinary frequency, urgency and urinary incontinence and to promote bladder emptying in the absence of urinary tract obstruction. This structured review of the literature was undertaken to search for and appraise evidence to support or negate the hypothesis of this relationship. The search strategy was comprehensive and identified six relevant studies. Two of these had been conducted on an adult population and four studies involved children with constipation. These studies were appraised for methodological quality. It was found that sample sizes were small and evidence was inconsistent. Variable methods of reporting meant that data were not able to be pooled for meta-analysis.
Based on the limited and conflicting evidence, it is recommended that further research be undertaken to identify any correlation between bowel and bladder function.

Low correlation between self-report and medical record documentation of urinary tract infection symptoms.

BACKGROUND Correlations between symptom documentation in medical records and patient self-report (SR) vary depending on the condition studied. Patient symptoms are particularly important in urinary tract infection (UTI) diagnosis, and this correlation for UTI symptoms is currently unknown. METHODS This is a cross-sectional survey study in hospitalized patients with Escherichia coli bacteriuria. Patients were interviewed within 24 hours of diagnosis for the SR of UTI symptoms. We reviewed medical records for UTI symptoms documented by admitting or treating inpatient physicians (IPs), nurses (RNs), and emergency physicians (EPs). The level of agreement between groups was assessed using Cohen κ coefficient. RESULTS Out of 43 patients, 34 (79%) self-reported at least 1 of 6 primary symptoms. The most common self-reported symptoms were urinary frequency (53.5%); retention (41.9%); flank pain, suprapubic pain, and fatigue (37.2% each); and dysuria (30.2%). Correlation between SR and medical record documentation was slight to fair (κ, 0.06-0.4 between SR and IPs and 0.09-0.5 between SR and EDs). Positive agreement was highest for dysuria and frequency. CONCLUSION Correlation between self-reported UTI symptoms and health care providers' documentation was low to fair. Because medical records are a vital source of information for clinicians and researchers and symptom assessment and documentation are vital in distinguishing UTI from asymptomatic bacteriuria, efforts must be made to improve documentation.

Development and validation of a pregnancy symptoms inventory

Background Physical symptoms are common in pregnancy and are predominantly associated with normal physiological changes. These symptoms have a social and economic cost, leading to absenteeism from work and additional medical interventions. There is currently no simple method for identifying common pregnancy related problems in the antenatal period. A validated tool, for use by pregnancy care providers would be useful. The aim of this study was to develop and validate a Pregnancy Symptoms Inventory for use by health professionals. Methods A list of symptoms was generated via expert consultation with health professionals. Focus groups were conducted with pregnant women. The inventory was tested for face validity and piloted for readability and comprehension. For test-re-test reliability, the tool was administered to the same women 2 to 3 days apart. Finally, midwives trialled the inventory for 1 month and rated its usefulness on a 10cm visual analogue scale (VAS). Results A 41-item Likert inventory assessing how often symptoms occurred and what effect they had, was developed. Individual item test re-test reliability was between .51 to 1, the majority (34 items) scoring ≥0.70. The top four “often” reported symptoms were urinary frequency (52.2%), tiredness (45.5%), poor sleep (27.5%) and back pain (19.5%). Among the women surveyed, 16.2% claimed to sometimes or often be incontinent. Referrals to the incontinence nurse increased > 8 fold during the study period. Conclusions The PSI provides a comprehensive inventory of pregnancy related symptoms, with a mechanism for assessing their effect on function. It was robustly developed, with good test re-test reliability, face validity, comprehension and readability. This provides a validated tool for assessing the impact of interventions in pregnancy.

Cyclosporine A in the treatment of Interstitial Cystitis

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic urinary bladder disorder of unknown etiology characterized by symptoms of bladder pain and urinary frequency. PBS/IC is a chronic disease in which drug therapy has not led to significant success over the course of time. If the symptoms of PBS/IC are refractory to standard treatments, a possible cure might demand surgical intervention involving cystectomy. The eventual autoimmune etiology in mind, immunosuppressive drug therapy with cyclosporine A (CyA) was started to patients with refractory PBS/IC. CyA is a potent anti-inflammatory drug, a calcineurin inhibitor which inhibits T lymphocyte IL-2 produc-tion. T cells are present in abundance in inflammation of the bladder in PBS/IC. On the basis of a pilot, short-term study with CyA on PBS/IC, use of CyA was continued empirically over the long term. We conducted a prospective, randomized, six-month study in 64 patients comparing the effect of CyA with the FDA approved treatment, pentosan polysulfate sodium (PPS). We measured the drug effect on patient s symptoms, the potassium sensitivity test, and on urinary biomarkers. We further tested the impact of CyA, PPS, DMSO and BCG therapy on a health-related quality of life questionnaire and evaluated the response rate to treatment with these therapies. Long-term use of CyA was safe and effective in PBS/IC patients. The good clinical effect matured individually during the years in which CyA was continued. Cessation of medication led to the reappearance of symptoms, and restarting CyA to renewed alleviation, so that CyA was administered as continuous medication. The response rate to CyA increased during the study period, comprising 75% of CyA patients at six months. 19% of patients responded to PPS therapy. Adverse effects were more common in the CyA group, underlining the importance of monitoring the drug safety and appropriate titration of the dose. The potassium sensitivity test is positive in the majority of PBS/IC patients. Successful therapy of PBS/IC can alter nerve sensitivity to external potassium. This effect was seen more often after CyA therapy. Successful treatment of PBS/IC with CyA resulted to decreasing urinary levels of EGF. IL-6 levels in urine were higher among older patient with a longer history of PBS/IC. In these patients, reduced levels of urinary IL-6 were measured after CyA therapy. Patients who experience the best treatment response have improved quality of life according to the post-treatment health-related quality of life (HRQOL) questionnaire. CyA had more impact on the ma-jority of the aspects of QoL than PPS. Despite DMSO therapy being more successful than BCG in the count of responders, DMSO and BCG had equal effects on the HRQOL questionnaire.

The impact of first pregnancy and delivery on pelvic floor dysfunction

Background: The first childbirth has the greatest impact on a woman’s pelvic floor when major changes occur. The aim of this study was to comprehensively describe pelvic floor dysfunction (PFD) in young nulliparous women, and its correlation with postnatal pathology. Methods: A prospective study was performed at Cork University Maternity Hospital, Ireland. Initially 1484 nulliparous women completed the validated Australian Pelvic Floor Questionnaire at 15 weeks’ gestation and repeatedly at one year postnatally (N=872). In the second phase, at least one year postnatally, 202 participants without subsequent pregnancies attended the clinical follow up which included: pelvic organ prolapse quantification, a 3D-Transperineal ultrasound scan and collagen level assessment. Results: A high pre-pregnancy prevalence of various types of PFD was detected, which in the majority of cases persisted postnatally and included multiple types of PFD. The first birth had a negative impact on severity of pre-pregnancy symptoms in <15% of cases. Apart from prolapse, vaginal delivery, including instrumental delivery did not increase the risk of PFD symptoms, where as Caesarean section was protective for all types of PFD. The first birth had a bigger impact on pre-existing symptoms of overactive bladder compared to stress urinary incontinence. Pelvic organ prolapse is extremely prevalent in young primiparous women, however usually it is low grade and asymptomatic. Congenital factors and high collagen type III levels play an important role in the aetiology of pelvic organs prolapse. Levator ani trauma is present in one in three women after the first pregnancy and delivery. Conclusion: The main damage to the pelvic floor most likely occurs due to an undiagnosed congenital intrinsic weakness of the pelvic floor structures. PFD is highly associated with first childbirth, however it seems that pregnancy and delivery are contributing factors only which unmask the congenital intrinsic weakness of the pelvic floor support.

The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer

Purpose: The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity.

Methods: Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2 cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full.

Results: Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p = 0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p = 0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT.

Conclusions: Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Phase II clinical study of an association for the treatment of interstitial cystitis (Cystex (R))

Painful bladder syndrome associated with interstitial cystitis (PBS/IC) is a clinical condition characterized pelvic pain, urinary urgency, and urinary frequency. In this study, 22 patients were assigned to make two visits over a three weeks period. The patients were randomly, double-blinded assigned in two groups. The first group received Cystex (R) capsules. The second group received placebo capsules. Two capsules were taken three times a day away from meals. The change from baseline in the O'Leary-Sant IC symptom and problem index was the primary outcome parameter. Changes in functional bladder capacity and intensity of pain and urgency have been chosen as secondary outcome parameters. Mood as well as physical and sexual activity were rated by 10 questions on a scale 0 to 6. The ratings were analyzed and the average for each patient in both groups Cystex (R) and placebo was determined as the quality of life index. For the primary outcome there was a statistically significant difference between the groups. Mean symptom score-sum decreased from 28.4 to 20.5 in the Cystex (R) group compared with 29.5 to 26.8 in the placebo group (p<0.05). For the secondary end points, pain and urgency intensity improved statistically significantly in the Cystex (R) group compared with the placebo group (p<0.05). The frequency and functional bladder capacity improved to greater degree in the Cystex (R) group. The differences were statistically significant for comparison of frequency (p<0.05) and not for functional bladder capacity (p>0.05). In our study, Cystex (R) enhanced quality of life over the placebo showing a statistically significant. This trial have shown that the efficacy and safety of therapy with Cystex (R) in the treatment of interstitial cystitis and is an alternative for patients suffering from this pathology. Therefore, it can be concluded that the composition of Cystex (R), increased the quality of life in treated patients.

Treatments for invasive carcinoma of the cervix: What are their impacts on the pelvic floor functions?

Aims: Describe the impact of surgery, radiotherapy and chemoradiation in the pelvic floor functions in cervical cancer patients. Materials and Methods: A prospective study with women submitted to radical hysterectomy (RH) (n = 20),exclusive radiotherapy (RT) (n= 20)or chemoradiation (CT/RT)(n = 20)for invasive cervical cancer. Urinary, intestinal and sexual function, as well as vaginal length and pelvic floor musclecontraction were evaluated. Comparisons between groups were performed by Kruskal-Wallis and Chi-square tests (p < 0.05). Results: The groups were similar in stress urinary incontinence incidence (p = 0.56), urinary urgency (p = 0.44),urge incontinence (p = 0.54),nocturia(p = 0.53), incomplete bowel emptying (p = 0.76),bowel urgency(p = 0.12)and soilage(p = 0.43). The CT/ RT group presented a higher urinary frequency(p < 0.001)and diarrhea(p = 0.025). Patients in the RH group were more sexually active(p = 0.01) and experienced less dyspareunia (p = 0.021). Vaginal length was shorter in RT group (5.5 ± 1.9 cm) and CT/ RT(.3 ± 1.5 cm) than in the RH group (7.4 ± 1.1 cm) (p < 0.001). Pelvic floor muscle contraction was similar (p = 0.302). Conclusions: RT and CT/RT treatment for cervical carcinoma are more associated to sexual and intestinal dysfunctions.

Phase II clinical study of an association for the treatment of interstitial cystitis (CYSTEX)

Painful bladder syndrome associated with interstitial cystitis (PBS/IC) is a clinical condition characterized pelvic pain, urinary urgency, and urinary frequency. In this study, 22 patients were assigned to make two visits over a three weeks period. The patients were randomly, double-blinded assigned in two groups. The first group received Cystex® capsules. The second group received placebo capsules. Two capsules were taken three times a day away from meals. The change from baseline in the O’Leary-Sant IC symptom and problem index was the primary outcome parameter. Changes in functional bladder capacity and intensity of pain and urgency have been chosen as secondary outcome parameters. Mood as well as physical and sexual activity were rated by 10 questions on a scale 0 to 6. The ratings were analyzed and the average for each patient in both groups Cystex® and placebo was determined as the quality of life index. For the primary outcome there was a statistically significant difference between the groups. Mean symptom score-sum decreased from 28.4 to 20.5 in the Cystex® group compared with 29.5 to 26.8 in the placebo group (p<0.05). For the secondary end points, pain and urgency intensity improved statistically significantly in the Cystex® group compared with the placebo group (p<0.05). The frequency and functional bladder capacity improved to greater degree in the Cystex® group. The differences were statistically significant for comparison of frequency (p<0.05) and not for functional bladder capacity (p>0.05). In our study, Cystex® enhanced quality of life over the placebo showing a statistically significant. This trial have shown that the efficacy and safety of therapy with Cystex® in the treatment of interstitial cystitis and is an alternative for patients suffering from this pathology. Therefore, it can be concluded that the composition of Cystex®, increased the quality of life in treated patients.

Estimulação elétrica com eletrodos não implantáveis no tratamento da bexiga hiperativa em adultos: revisão sistemática de ensaios clínicos randonizados

Pós-graduação em Bases Gerais da Cirurgia - FMB

Age-related trends in urinary excretion of bisphenol A in Australian children and adults : evidence from a pooled sample study using samples of convenience

Bisphenol A (BPA or 4,4’-(propane-2,2-diyl)diphenol) is a chemical intermediate in the production of polycarbonate and epoxy resins, and used in a wide range of applications. BPA has attracted significant attention in the past decade due to its frequency of detection in human populations worldwide, demonstrated animal toxicity and potential impact on human health, particularly during critical periods of development. The aim of this study was to perform a preliminary assessment of age-related trends in urinary concentration and to estimate daily excretion of BPA in Australian children (aged (>0 – <5 years) and adults (≥15 – <75 years). This was achieved using 79 samples pooled by age and gender, created from 868 individual samples of convenience collected as part of routine, community-based pathology testing. Total BPA was analyzed using online-SPE-LC-MS/MS and detected in all samples with a range of 0.65 – 265 ng/ml. No significant differences were observed between males and females. A urine flow model was constructed from published values and used to provide an estimate of daily excretion per unit bodyweight for each pooled sample. The daily excretion estimates ranged from 26.2 – 18200 ng/kg-d for children; and 20.1 – 165 ng/kg-d for adults. Urinary concentrations and estimated excretion rates were inversely associated with age, and estimated daily excretion rates in infants and young children were significantly higher than in adults (geometric mean: 107 and 47.0 ng/kg-d, respectively). Higher excretion of BPA in children may be explained by their higher food consumption relative to body weight compared to adults and adolescents, and may also reflect alternative exposure pathways and sources. Keywords: bisphenol A, biomonitoring, children, urine flow, Australia

Characterization of genomic diversity in extraintestinal pathogenic Escherichia coli (ExPEC) and development of a diagnostic DNA microarray for the differentiation of ExPEC isolates causing urinary tract infections

Extraintestinal pathogenic Escherichia coli (ExPEC) represent a diverse group of strains of E. coli, which infect extraintestinal sites, such as the urinary tract, the bloodstream, the meninges, the peritoneal cavity, and the lungs. Urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC), the major subgroup of ExPEC, are among the most prevalent microbial diseases world wide and a substantial burden for public health care systems. UTIs are responsible for serious morbidity and mortality in the elderly, in young children, and in immune-compromised and hospitalized patients. ExPEC strains are different, both from genetic and clinical perspectives, from commensal E. coli strains belonging to the normal intestinal flora and from intestinal pathogenic E. coli strains causing diarrhea. ExPEC strains are characterized by a broad range of alternate virulence factors, such as adhesins, toxins, and iron accumulation systems. Unlike diarrheagenic E. coli, whose distinctive virulence determinants evoke characteristic diarrheagenic symptoms and signs, ExPEC strains are exceedingly heterogeneous and are known to possess no specific virulence factors or a set of factors, which are obligatory for the infection of a certain extraintestinal site (e. g. the urinary tract). The ExPEC genomes are highly diverse mosaic structures in permanent flux. These strains have obtained a significant amount of DNA (predictably up to 25% of the genomes) through acquisition of foreign DNA from diverse related or non-related donor species by lateral transfer of mobile genetic elements, including pathogenicity islands (PAIs), plasmids, phages, transposons, and insertion elements. The ability of ExPEC strains to cause disease is mainly derived from this horizontally acquired gene pool; the extragenous DNA facilitates rapid adaptation of the pathogen to changing conditions and hence the extent of the spectrum of sites that can be infected. However, neither the amount of unique DNA in different ExPEC strains (or UPEC strains) nor the mechanisms lying behind the observed genomic mobility are known. Due to this extreme heterogeneity of the UPEC and ExPEC populations in general, the routine surveillance of ExPEC is exceedingly difficult. In this project, we presented a novel virulence gene algorithm (VGA) for the estimation of the extraintestinal virulence potential (VP, pathogenicity risk) of clinically relevant ExPECs and fecal E. coli isolates. The VGA was based on a DNA microarray specific for the ExPEC phenotype (ExPEC pathoarray). This array contained 77 DNA probes homologous with known (e.g. adhesion factors, iron accumulation systems, and toxins) and putative (e.g. genes predictably involved in adhesion, iron uptake, or in metabolic functions) ExPEC virulence determinants. In total, 25 of DNA probes homologous with known virulence factors and 36 of DNA probes representing putative extraintestinal virulence determinants were found at significantly higher frequency in virulent ExPEC isolates than in commensal E. coli strains. We showed that the ExPEC pathoarray and the VGA could be readily used for the differentiation of highly virulent ExPECs both from less virulent ExPEC clones and from commensal E. coli strains as well. Implementing the VGA in a group of unknown ExPECs (n=53) and fecal E. coli isolates (n=37), 83% of strains were correctly identified as extraintestinal virulent or commensal E. coli. Conversely, 15% of clinical ExPECs and 19% of fecal E. coli strains failed to raster into their respective pathogenic and non-pathogenic groups. Clinical data and virulence gene profiles of these strains warranted the estimated VPs; UPEC strains with atypically low risk-ratios were largely isolated from patients with certain medical history, including diabetes mellitus or catheterization, or from elderly patients. In addition, fecal E. coli strains with VPs characteristic for ExPEC were shown to represent the diagnostically important fraction of resident strains of the gut flora with a high potential of causing extraintestinal infections. Interestingly, a large fraction of DNA probes associated with the ExPEC phenotype corresponded to novel DNA sequences without any known function in UTIs and thus represented new genetic markers for the extraintestinal virulence. These DNA probes included unknown DNA sequences originating from the genomic subtractions of four clinical ExPEC isolates as well as from five novel cosmid sequences identified in the UPEC strains HE300 and JS299. The characterized cosmid sequences (pJS332, pJS448, pJS666, pJS700, and pJS706) revealed complex modular DNA structures with known and unknown DNA fragments arranged in a puzzle-like manner and integrated into the common E. coli genomic backbone. Furthermore, cosmid pJS332 of the UPEC strain HE300, which carried a chromosomal virulence gene cluster (iroBCDEN) encoding the salmochelin siderophore system, was shown to be part of a transmissible plasmid of Salmonella enterica. Taken together, the results of this project pointed towards the assumptions that first, (i) homologous recombination, even within coding genes, contributes to the observed mosaicism of ExPEC genomes and secondly, (ii) besides en block transfer of large DNA regions (e.g. chromosomal PAIs) also rearrangements of small DNA modules provide a means of genomic plasticity. The data presented in this project supplemented previous whole genome sequencing projects of E. coli and indicated that each E. coli genome displays a unique assemblage of individual mosaic structures, which enable these strains to successfully colonize and infect different anatomical sites.