MFSD7c functions as a transporter of choline at the blood-brain barrier.

Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c-/-) mice and cell-based assays to reveal that MFSD7c is a choline transporter at the blood-brain barrier (BBB). We performed comprehensive metabolomics analysis and detected differential changes of metabolites in the brains and livers of Mfsd7c-/-embryos. Particularly, we found that choline-related metabolites were altered in the brains but not in the livers of Mfsd7c-/- embryos. Thus, we hypothesized that MFSD7c regulates the level of choline in the brain. Indeed, expression of human MFSD7c in cells significantly increased choline uptake. Interestingly, we showed that choline uptake by MFSD7c is greatly increased by choline-metabolizing enzymes, leading us to demonstrate that MFSD7c is a facilitative transporter of choline. Furthermore, single-cell patch clamp analysis showed that the import of choline by MFSD7c is electrogenic. Choline transport function of MFSD7c was shown to be conserved in vertebrates, but not in yeasts. We demonstrated that human MFSD7c is a functional ortholog of HNM1, the yeast choline importer. We also showed that several missense mutations identified in patients exhibiting Fowler syndrome had abolished or reduced choline transport activity. Mice lacking Mfsd7c in endothelial cells of the central nervous system suppressed the import of exogenous choline from blood but unexpectedly had increased choline levels in the brain. Stable-isotope tracing study revealed that MFSD7c was required for exporting choline derived from lysophosphatidylcholine in the brain. Collectively, our work identifies MFSD7c as a choline exporter at the BBB and provides a foundation for future work to reveal the disease mechanisms of Fowler syndrome.

Do men adapt to lower urinary tract symptoms? An 11-year longitudinal study of male urinary urgency and associated bother.

OBJECTIVE: The study objective is to evaluate prognosis and predictors of bother caused by urinary urgency among middle-aged and older men. MATERIAL AND METHODS: A population-based sample of men born in 1974, 1964, 1954, 1944, 1934 and 1924 was followed-up from 2004 to 2015. The course of urgency and associated bother was evaluated with the Danish Prostatic Symptom Score at baseline and follow-up. Logistic regression was utilized to explore risk factors of increased bother at follow-up. RESULTS: A total of 2,480 men (39%) who had responded at baseline and follow-up were included in the study. Of them, 1,056 men (43%) had persistent mild urgency and 132 men (5%) persistent moderate or severe urgency at follow-up. The proportions of men experiencing at least moderate bother due to persistent urgency at follow-up were 6% (95% confidence interval 4.5-7.3) of those with mild and 79% (71.7-85.9) of the men with moderate or severe urgency. In multivariable-adjusted logistic regression, moderate to severe urgency was strongly associated with bother (odds ratio, OR 55.2, 95% CI 32.1-95.2). Other predictors of bother included cardiac disease (OR 1.8, 95% CI 1.0-31.1), pulmonary disease (OR 1.9, 95% CI 1.1-3.5) and medical treatment (OR 2.7, 95% CI 1.6-4.6). CONCLUSIONS: Most men with urinary urgency have mild symptoms and bother. Only one out of five men with persistent moderate or severe urgency adapt to the symptoms. Men with a history of medical treatment for lower urinary tract symptoms (LUTS) or impaired cardiopulmonary health are more likely to experience bother from urinary urgency.

Development and construction of an open-platform, open-source low-cost portable uroflowmeter: The OpenFlow device.

BACKGROUND: Uroflowmetry is useful to screen for and manage many voiding disorders. Home-based uroflowmetry might better represent the patient's true voiding pattern and be more widely adopted if an accurate low-cost portable device was available. OBJECTIVE: Development and initial evaluation of an open-platform, open-source low-cost portable uroflowmeter. MATERIALS AND METHODS: We designed and built an uroflowmeter comprising of a load cell and digital memory card unit connected to a programmable microcontroller board mounted upon a 3D printed frame. It generated date-stamped tables which were processed and plotted. Twenty urologists were recruited to assess the device. Each participant received the equipment that was returned, along with a bladder diary, after at least 24 consecutive hours of homemade uroflowmetry recording. Additionally, were assessed with the International Prostatic Symptom Score (I-PSS) and Peeling diagram, whereas the device's ease of use, robustness, and portability were evaluated with a Likert-type questionnaire. Two experienced urodynamicists independently evaluated the tracings' quality rated with a 3° ordinal scale: (1) Interpretable without artifacts; (2) Interpretable with artifacts; (3) Uninterpretable. RESULTS: Participants' median age was 36.6 years old, none having an I-PSS > 5 or Peeling > 2. Overall 138 voidings were recorded (77 daytime, 61 nightly episodes). The device's ease of use, robustness, and portability obtained maximum score in 80% of evaluations. Most (98%) of the tracings were considered interpretable. Limitations included its small study population and short monitoring times. CONCLUSION: The construction of a cheap (<50 USD), accurate user-friendly portable uroflowmeter proved feasible, which could facilitate access to portable uroflowmetry.

Lower urinary tract symptoms in young-middle aged males with a diagnosis of obstructive sleep apnea syndrome.

BACKGROUND: The aim of the current study is to measure the prevalence and the potential role of International Prostate Symptom Score (IPSS) score as a predictor of obstructive sleep apnea syndrome (OSAS) in male experienced lower urinary tract symptoms (LUTS). METHODS: A cross-sectional web-based Italian survey was administered via Google Forms between July 17 and October 31, 2022. The urinary functioning was measured through the IPSS questionnaire. Specifically, we considered symptoms occurring more than "about half the time" (score ≥ 3) as bothering symptoms. Multivariable logistic regression models (LRMs) adjusting for age, body mass index (BMI), International Index of Erectile Function-5, IPSS, and hypertension were fitted to predict OSAS in the cohort of men responding to the survey and experiencing LUTS. RESULTS: Overall, 58 (24.4%) patients had a confirmed diagnosis of OSAS. The overall median IPSS was 5 (inter quartile range [IQR]: 3-8), respectively. According to IPSS items, 24 (10%), 44 (18.4%), 12 (5%), 12 (5%), 12 (5%), 11 (4.6%), 63 (26.4%) patients exhibit incomplete bladder emptying, urinary frequency, intermittency, urgency, weak stream, straining, nocturia with a score ≥ 3, respectively. After multivariable LRMs predicting the developing OSAS, age (odds ratio [OR]: 1.09, p < 0.001), BMI (OR:1.12, p < 0.001) and IPSS total score (OR:1.08, p = 0.02) were independent predicting factors. CONCLUSION: This analysis revealed that the IPSS total score, age, and BMI are independent predictors of OSAS in males. In this context, the use of IPSS in daily practice could be helpful in assessing the LUTS presence and in supporting physicians to identify a hidden sleep apnea condition.

The effect of botulinum toxin A in children with non-neurogenic therapy-refractory dysfunctional voiding - A systematic review.

INTRODUCTION: Dysfunctional voiding (DV) is a habitual voiding disorder caused by involuntary contraction or non-relaxation of the external urethral sphincter (EUS) during voiding. This contraction causes high post-void residuals (PVR), urinary incontinence and urinary tract infections (UTIs). Various treatments for DV are available, but some children do not respond. Intersphincteric botulinum toxin-A (BTX-A) may be a possible treatment for therapy-refractory children with DV. OBJECTIVE: The aim of this systematic review is to summarize the effects and safety of intersphincteric BTX-A as a treatment for therapy-refractory DV in children. METHODS: A systematic search in Embase, MEDLINE, Cochrane, and Web of Science databases was performed. Studies reporting on the usage of intersphincteric BTX-A as a treatment for DV in children were included. Data on PVR, maximum flow rate (Qmax), repeat injections and complications were extracted. RESULTS: From a total of 277 articles, five cohort studies were identified, reporting on 78 children with DV of whom 53 were female (68 %) and 25 were male (32 %). Sample sizes ranged from ten to twenty patients. Mean or median age at the time of intervention ranged from 8 to 10.5 years. Meta-analysis could not be performed due to lack of data. The narrative synthesis approach was therefore used to summarize the results. All studies showed significant decrease in PVR after BTX-A injection. Three studies showed a 33-69 % improvement on incontinence after BTX-A injection. Less UTIs were reported after treatment. A temporary increase in incontinence, UTIs and transitory numbness to the gluteus muscle were reported as side-effects. CONCLUSIONS: BTX-A could be a safe and effective treatment option for therapy-refractory DV in children by reducing PVR, UTIs and incontinence. Hereby, the synergistic effect of BTX-A and urotherapy should be emphasized in future management. Furthermore, this study identified gaps in current knowledge that are of interest for future research.

Microbiologist in the clinic: coitally related symptoms with negative urine cultures.

In this first episode of the Microbiologist in the Clinic series, clinicians and laboratory scientists share their perspectives about a 30 y/o woman, who is seeking specialty consultation for frequent episodes of urinary urgency, frequency, and dysuria, which respond to short courses of antibiotics. Although her home dipsticks suggest that she has a UTI, and her urinalysis typically has a moderate number of white blood cells, her urine cultures are always negative. The challenges of this clinical presentation are discussed with evidence for evaluation and treatment.

[Noninvasive peripheral magnetic stimulation in the treatment of neurogenic urination disorders in children]. / Neinvazivnaya perifericheskaya magnitnaya stimulyatsiya v terapii neirogennykh rasstroistv mocheispuskaniya u detei.

Neurogenic urination disorders in children are often clinically represented by urinary incontinence (UI). The prevalence of UI reaches 8.6%, but tends to decrease in frequency with age. One of the methods of non-drug therapy of UI is extracorporeal magnetic stimulation (ExMI) - a type of non-invasive peripheral magnetic stimulation, which is widely used in adult urological practice. However, the effectiveness of the method in children has not been studied. OBJECTIVE: To study the effectiveness and safety of ExMI in the rehabilitation of children with neurogenic UI. MATERIAL AND METHODS: A prospective open randomized comparative clinical trial included 75 children (from 5 years to 16 years and 6 months) with neurogenic UI, who were divided by simple randomization into a main group (n=39), who received a standard rehabilitation and ExMI program for 21 days, and a comparison group (n=36), in which the standard rehabilitation program did not include the use of ExMI. RESULT AND DISCUSSION: A prospective open randomized comparative study revealed that the clinical effectiveness of the ExMI method in the complex rehabilitation of children with neurogenic UI is 94.8%, which is 25.4% higher than in the comparison group. After treatment, patients in the main group had a noticeable decrease in UI episodes, an increase in the micturition volume, and an improvement in the quality of life. Patients with various background neurological pathology responded to treatment, which indicates the common pathogenetic mechanisms of the development of LUTS in these conditions and the independence of the final effect from the basic diagnosis. CONCLUSION: The use of the perineal ExMI method in children with neurogenic UI increases the effectiveness of rehabilitation and is a promising and safe direction of rehabilitation treatment.

[Sacral neuromodulation for bladder voiding dysfunction: Experience at a French university center]. / Neuromodulation sacrée pour trouble de la vidange vésicale : expérience d'un centre universitaire français.

OBJECTIVE: To report the experience of a university hospital center with sacral neuromodulation for patients with bladder voiding disorders. MATERIAL AND METHODS: All patients who underwent sacral neuromodulation between 1998 and 2022 for bladder voiding disorders were included. Medical records were analyzed retrospectively, and population, efficacy and follow-up data were collected. RESULTS: A total of 134 patients underwent test implantation and 122 patients were analyzed. 68 patients (56%) were implanted with a definitive neuromodulation device. Mean age was 43±16 years and BMI 25.5±5.4kg/m2. 74% were women. Bladder voiding disorder was due to sphincter hypertonia in 51% of cases, with associated bladder hypocontractility in 29%. The spontaneous micturition rate after implantation increased from 34% to 92%. Implantation results appeared to be better in patients with sphincter hypertonia, whether or not associated with bladder hypocontractility. The benefit was most often present with a frequency of 5Hz (54.4%). Side-effects were present in 52% of cases at 5 years, and in 85% of cases were pain in relation to the implanted devices. They resolved under medical treatment or after revision of the device (27% of cases at 5 years). CONCLUSION: SNM is effective in micturition recovery, but has side effects. Urodynamic mechanism and etiology may provide clues for modulating NMS box settings and determining predictive factors for NMS success. Data from other centers are needed to identify reliable predictive factors.

Prevalence and Bother of Postvoid Dribbling and Urine Spraying or Splitting: Survey of a General Gynecology Population.

IMPORTANCE: Postvoid dribbling is described well for men in urologic literature but is poorly defined for women, especially in those not presenting for urogynecologic care. OBJECTIVE: The objective was to assess prevalence and bother of postvoid dribbling, urine spraying (ie, deviation of the urine stream), and other bothersome voiding/storage symptoms in a general gynecology population. STUDY DESIGN: This was an anonymous cross-sectional survey study of women presenting to academic general gynecology practices for benign gynecologic care or well-woman visits; patients were not presenting for urinary incontinence or voiding dysfunction. A questionnaire was used to assess the presence and perceptions of voiding behavior and urinary symptoms with an emphasis on postvoid dribbling and urine spraying. The questionnaire included both the validated Questionnaire for Urinary Incontinence Diagnosis and nonvalidated questions. RESULTS: Nonpregnant adult women (N = 355) were surveyed. The median age was 43 years (interquartile range, 33-51 years). The sample was 45% White, 23% Black, 3% Asian, and 13% other. Furthermore, 39% were Latina; 68%, parous; and 28%, postmenopausal. The prevalence (95% confidence interval) of immediate postvoid dribbling was 186 of 327 or 57% (51-62%), and of these, it was at least somewhat bothersome in 37% but moderately-to-quite-a-bit bothersome in 8%. Urine spraying occurred in 222 of 333 or 67% (61-72%), and of these, it was at least somewhat bothersome in 53% but moderately-to-quite-a-bit bothersome in 17%. Approximately 20% reported stress and/or urgency urinary incontinence; both postvoid dribbling and urine spraying were highly associated with these symptoms. CONCLUSIONS: This study of women seeking benign gynecologic care shows a high prevalence of postvoid dribbling and urine spraying symptoms. However, moderate-or-greater bother was relatively uncommon.

Overactive bladder syndrome symptoms in youth with abdominal pain-associated disorders of gut-brain interaction.

The purpose of the current study was to assess the frequency of overactive bladder syndrome (OBS) symptoms and their relationship to gastrointestinal symptoms in youth with abdominal pain-associated disorders of gut-brain interaction (AP-DGBI). This is a retrospective study of 226 youth diagnosed with an AP-DGBI. As part of standard care, all patients completed a symptom questionnaire regarding gastrointestinal and non-gastrointestinal symptoms including increased urinary frequency, nighttime urination, and urinary urgency. Overall, 54% of patients reported at least one OBS symptom. Increased frequency of urination was reported by 19%, urinary urgency by 34%, and nighttime urination by 36%. Increased frequency of urination and urinary urgency were associated with a change in stool form, a change in stool frequency, and in those fulfilling criteria for IBS. Increased frequency of urination was reported more frequently in those reporting predominantly loose stools (33% vs. 12%). Urinary symptoms are common in youth with AP-DGBI. Increased urinary frequency and urinary urgency are specifically associated with IBS, with increased urinary frequency being primarily associated with diarrhea predominant IBS. Further studies are needed to determine the impact of OBS on AP-DGBI severity and quality of life, and whether they impact DGBI treatment.

Is it time to reconsider how we document pediatric uroflow studies?: A study from the SPU Voiding Dysfunction task force.

BACKGROUND: Uroflowmetry is a non-invasive study used in the diagnosis and monitoring of treatment response for lower urinary tract disorders. For optimal clinical utility, uroflow studies rely on careful clinical interpretation by a trained provider, but currently there is a lack of accepted standardized normal values for the measured uroflow parameters in children. The International Children's Continence Society proposed standardizing the terminology for uroflow curve shapes. However, the patterning of curves is largely at the physician's subjective discretion. OBJECTIVES: The aims of this study were to understand inter-rater reliability in interpreting uroflow curves and to define characteristics of uroflow curves that could be used to provide definitive criteria for uroflowmetry parameters. METHODS: All members of the SPU Voiding dysfunction Task Force were invited to contribute deidentified uroflows to a centralized HIPAA complaint receiving database. All studies were then distributed to all raters for review. Each observer's findings were recorded according to ICCS criteria (ICCS), additional readings were done using a previously reported system which defined curves as smooth or fractionated (SF) and whether the shape resembled a bell, tower, or plateau (BTP). Flow indexes (Qact/Qest) (FI) for Qmax and Qavg were generated using formulas previously reported for children 4-12 and for patients≥12 years. RESULTS: A total of 119 uroflow studies were read by 7 raters and curves were contributed from 5 sites. Kappa scores for the 5 readers from different institutions were 0.34 and 0.28 for the ICCS and BTP methods, respectively (both considered fair agreement). Kappa for smooth and fractionated curves was 0.70 (for each; considered substantial agreement), which were the two highest agreement scores obtained throughout the study. Discriminant analysis (DA) revealed that the FI Qmax was the dominant vector, and that the ICCS uroflow parameters have a total of 42.8% prediction rate in the training sample. Using DA of a smooth/fractionated system, the total prediction rates were 72% and 65.5% for smooth and fractionated, respectively. DISCUSSION: Given the poor inter-rater agreement for analyzing uroflow curve pattern based on ICCS criteria in this study and others, one may find it reasonable to consider alternative approaches to describing and characterizing uroflow curves. Our study is limited by lack of EMG and post-void residual data. CONCLUSIONS: For a more objective uroflow interpretation and comparison of studies among different centers, we recommend using our proposed system (based on FI, and smooth vs. fractionated curve pattern), which is more reliable.

[Melanosis of the bladder-a rare diagnosis]. / Melanose der Harnblase ­ eine Rarität.

Melanosis of the urinary bladder is an extremely rare benign condition in which melanin deposits occur in the urothelial and stromal cells. We report such a case in which melanosis of the urinary bladder was detected in a 55-year-old woman with known multiple sclerosis during an extended workup due to urinary urgency complaints. The findings were confirmed by biopsy.

Personalized Pre-clinic Nursing Telemedicine Visit: An Efficient and Efficacious Approach for Bowel and Bladder Dysfunction in Children.

OBJECTIVES: To evaluate the effectiveness and efficacy of a Registered Nurse (RN) led educational pre-clinic telephone call on compliance and outcomes in children with bowel and bladder dysfunction (BBD). METHODS: A retrospective chart review of a prospectively applied protocol in a single academic institution was performed for children aged 4-17 presenting with BBD. All children underwent a pre-clinic RN telemedicine visit where they were educated on pathophysiology of BBD, provided personalized urotherapy and bowel recommendations and instructed to complete pre-clinic questionnaires and voiding diaries. Patients were evaluated by a provider 4weeks following RN call. Data collected included compliance with forms, bowel management and need for imaging/testing, medications, and biofeedback. Patients were considered to improve with urotherapy alone if they were discharged from urology without the need for medications and/or biofeedback. RESULTS: In total, 277 patients completed an RN call and 224 patients attended a provider visit between December 2020 and June 2022. Mean age was 9.4years (3:1 Female to Male ratio). During the RN call, 154 (56%) patients had bowel management initiated. Of the 224 patients seen by a provider, 69% (n = 154) had symptom improvement or resolution with urotherapy alone. Thirty-eight patients (17%) enrolled in biofeedback with 7 (3%) completing all 8 sessions. Thirty-two patients (14%) required medication for daytime bladder symptoms. CONCLUSION: Our novel RN-led pre-clinic telemedicine visit demonstrates excellent compliance and patient outcomes for children with BBD and can reduce the use of unnecessary imaging, medications, and time-consuming treatments such as biofeedback.

The effect of prolapse surgery on voiding function.

INTRODUCTION AND HYPOTHESIS: Of women with symptomatic prolapse, 13-39% experience voiding dysfunction (VD). The aim of our observational cohort study was to determine the effect of prolapse surgery on voiding function. METHODS: Retrospective analysis of 392 women who underwent surgery between May 2005 and August 2020. All had a standardized interview, POP-Q, uroflowmetry and 3D/4D transperineal ultrasound (TPUS) pre-and postoperatively. Primary outcome was change in VD symptoms. Secondary outcomes were changes in maximum urinary flow rate (MFR) centile and post-void residual urine (PVR). Explanatory measures were change in pelvic organ descent as seen on POP-Q and TPUS. RESULTS: Of 392 women, 81 were excluded due to missing data, leaving 311. Mean age and BMI were 58 years and 30 kg/m2, respectively. Procedures performed included anterior repair (n = 187, 60.1%), posterior repair (n = 245, 78.8%), vaginal hysterectomy (n = 85, 27.3%), sacrospinous colpopexy (n = 170, 54.7%) and mid-urethral sling (MUS) (n = 192, 61.7%). Mean follow-up was 7 (1-61) months. Pre-operatively, 135 (43.3%) women reported symptoms of VD. Postoperatively, this decreased to 69 (22.2%) (p < 0.001), and of those, 32 (10.3%) reported de novo VD. The difference remained significant after excluding concomitant MUS surgery (n = 119, p < 0.001). Postoperatively, there was a significant decrease in mean PVR (n = 311, p < 0.001). After excluding concomitant MUS surgery, there was a significant increase in mean MFR centile (p = 0.046). CONCLUSIONS: Prolapse repair significantly reduces symptoms of VD and improves PVR and flowmetry.

Dysfunctional Voiding: Exploring Disease Transition From Childhood to Adulthood.

OBJECTIVE: To improve our transitional care, we explored how childhood dysfunctional voiding (DV) develops into adulthood. DV is a common condition in both children and adults. However, the long-term course of childhood DV into adulthood is unknown and treatment over the ages differs. METHODS: A cross-sectional follow-up was performed in a cohort of 123 females treated from 2000 to 2003 for childhood DV with urinary tract infections (UTIs) and/or daytime urinary incontinence (DUI). The main outcome was a staccato or intermittent urinary flow pattern, possibly indicating persistent or recurred DV according to the International Continence Society criteria. Flow patterns of healthy women were used to compare results. RESULTS: Twenty-five patients participated in this study, with a mean duration of 20.8 years after urotherapy. In 10/25 (40%) cases, a staccato or interrupted urinary flow pattern was found on the current measurement, compared to 5/47 (10.6%) in the control group. Around 50% (5/10) of the patients with a dysfunctional flow pattern reported UTIs and 50% (5/10) experienced DUI. In the group with a normal flow pattern, 2/15 (13%) reported UTIs and 9/15 (60%) DUI. The impact of DUI on quality of life was moderate to high in both groups. CONCLUSION: Our results show that 40% of females who had extensive urotherapy for DV in childhood, still have DV according to International Continence Society criteria as an adult, 56% still experience DUI, and 28% UTIs. These data should be taken into account in the counseling of patients and for guiding the process of transition into adulthood.