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The aim of this study is to examine the functional outcomes of ona-botulinum toxin A (BTX-A) injection into the external urethral sphincter (EUS) for female patients with nonneurogenic nonrelaxing sphincter as the underlying cause of voiding dysfunction (VD).A retrospective analysis was performed for all the patients with the urodynamic findings of higher than expected maximum urethral closure pressure (MUCP) who received their first injection during the study period. All patients were evaluated with preoperative videourodynamic study and urethral pressure profilometry and received 100 U of EUS BTX-A. Patients aged less than 18 years and those with neurogenic bladder were excluded. All patients were followed up with the free flow, postvoid residuals (PVR), and patient global impression of improvement (PGI-I) scale at 6 weeks and then at 3 monthly intervals.We identified 35 female patients with a mean age of 37.5 ± 15 years (range 18-72 years) with a mean follow-up of 20 months. More than 50% of patients had a history of prior surgical intervention and 28 (80%) patients were catheter dependent, a suprapubic catheterization, or clean intermittent self-catheterization. Mean MUCP was 97.1 ± 22 cm of water. After treatment with BTX-A, 21 (60%) patients were able to void per urethral (p = 0.02). The mean maximum flow rate (Qmax) improved from 8.8 to 11 mls/s and the mean PVR decreased from 200 to 149 mls (p lt; 0.05). On multivariate analysis, we identified high preoperative PVR, high preoperative actual MUCP, and previous surgical intervention (urethral dilatation, sacral neuromodulation, and pelvic surgery) as predictors of successful voiding restoration. The mean duration of response was 4.7 months, 46% of patients requested repeat injection, and 29% were established on maintenance injections. On the 5-point PGI-I score, 13 (37%), 12 (34%), and 10 (29%) patients reported good, some, and no improvement, respectively. Quality of life was also improved in 60% of patients. Two patients had transient stress urinary incontinence (for lt;6 weeks) and there were no significant long-lasting adverse events.EUS BTX-A is a valid treatment option for VD considering therapeutic options are limited. The patient must be made aware of the need for repeat treatments.

Aims To determine the bleeding risk in patients taking anticoagulants (AC) and antiplatelets (AP) before onabotulinumtoxinA (BoNT-A) injections and improve peri-operative decision making and counseling. Methods We performed a retrospective review of patients having intravesical BoNT-A in three teaching hospitals from January 2016 to July 2018. Demographic data, indication for intravesical BoNT-A injection, and side-effects of significant bleeding requiring intervention were recorded. Results Five hundred and thirty-two patients had intravesical BoNT-A injections during this time. Sixty-three patients of mean age 69 years (range 19-89) had a total of 114 separate rounds of BoNT-A injections whilst on treatment dose AC/AP therapy. Of the 63, there were 33 males, with 46 having idiopatic detrusor overactivity and 17 with neurogenic detrusor overactivity. Each patient had between 1 and 7 repeat injections during the studied period. AC/AP use across the 114 episodes included; aspirin 44, clopidogrel 37, warfarin 19, and NOAC (novel/non-vitamin K oral anticoagulant) 14. Patients on warfarin who had point of care testing all had international normalized ratio less than 3. BoNT-A dose varied from 100U to 300U-modal dosage was 200U.1/114(0.88%) injection episodes resulted in postinjection hematuria requiring overnight admission. This resolved spontaneously, with an overnight catheter. This patient was on rivaroxaban and had 300U of BoNT-A injected through 20 sites, on a background of previous prostate radiotherapy and self-catheterization. Conclusions Continuation of AP/AC therapy during intravesical BoNT-A injection treatment appears to be safe-with a 0.88% rate of spontaneously resolving hematuria.

Introduction In the development of terminology of the lower urinary tract (LUT), due to its increasing complexity, the terminology for male LUT surgery needs to be updated using a male-specific approach and via a clinically-based consensus report. Methods This report combines the input of members of the Standardization Committee of the International Continence Society in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 14 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Results A Terminology Report for male LUT and pelvic floor surgery, encompassing 149 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in male LUT surgery. Figures have not been included to avoid any preference or bias towards a specific procedure. Conclusions A consensus-based Terminology Report for male LUT surgery has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

AIMS To investigate typical pad weight gain (PWG) in asymptomatic women who have never reported any episodes of urinary incontinence. METHODS An observational study was performed by measuring the increase in weight of small sanitary pads worn by 35 healthy, female volunteers of a median age 36 (range, 23-56) years. Each pad was worn for a minimum of 5 h which is the typical maximum duration of an ambulatory urodynamics study. RESULTS The median duration of pad wear was 6 h (interquartile range [IQR], 5-8). The median PWG was 0.111 g (IQR, 0.047-0.255). The maximum recorded PWG was 0.621 g and the minimum was 0.012 g. PWG was not significantly affected by age, parity, years since last delivery, body mass index, or menopausal status. CONCLUSIONS PWG over a median duration of 6 h (IQR, 5-8) is typically

Aims To investigate the role of onabotulinumtoxinA (BTX-A) injections in patients with failed augmentation cystoplasty for neuropathic or idiopathic detrusor overactivity (NDO or IDO). Methods A retrospective review of all cystoplasty patients who underwent onabotulinumtoxinA injection at a tertiary center between 2008 and 2019 was performed. Details including indications and time from cystoplasty, video-urodynamic parameters, onabotulinumtoxinA dose, and clinical outcomes were analyzed. Telephone interview was performed for patients that requested repeat onabotulinumtoxinA injections. The interview included a modified PGIC7 and UDI6 questionnaires. A positive clinical response was considered improvement of overactive symptoms sufficient to merit repeat onabotulinumtoxinA injection and a modified PGIC7 of four or above. Results Thirty patients were identified (11 men and 19 women). The indications for augmentation were IDO (n = 18) or NDO (n = 12). Mean age at the time of cystoplasty was 42 years (range, 10-61). Interval between cystoplasty and initial onabotulinumtoxinA was 98 months (range, 3-271). Video-urodynamics before onabotulinumtoxinA revealed low compliance in 13 patients, DO in 22 patients, and combined low compliance/DO in 10. The median maximum cystometric bladder capacity was 338 mL (range, 77-570 mL). Thirteen patients responded to onabotulinumtoxinA injections. Higher peak DO pressure was associated with a significantly higher chance that the patient would experience benefit from the injections P = .026). The patients that responded to onabotulinumtoxin A underwent a total of 115 procedures (mean, 8.8 injections) over a mean 88 months (range, 20-157 months). Conclusions Forty-three percent of patients responded well to intra-detrusor onabotulinumtoxinA injections. This avoided the need for more invasive surgery and had a positive impact on their quality of life.

While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.

Inflammatory cells contribute to irreversible damage in pulmonary arterial hypertension (PAH). We hypothesized that in PAH, dysfunctional BMPR2 signaling in macrophages contributes to pulmonary vascular injury and phenotypic changes via proinflammatory cytokine production. Studies were conducted in: (1) Rosa26-rtTA2 3 X TetO7-Bmpr2delx4 FVB/N mice (mutant Bmpr2 is universally expressed, BMPR2 delx4 mice) given a weekly intra-tracheal liposomal clodronate injections for four weeks; and (2) LysM-Cre X floxed BMPR2 X floxed eGFP monocyte lineage-specific BMPR2 knockout (KO) mouse model (Bmpr2 gene expression knockdown in monocytic lineage cells) (BMPR2 KO ) following three weeks of sugen/hypoxia treatment. In the BMPR2 delx4 mice, increased right ventricular systolic pressure (RVSP; P

Aims An updated literature review on outcomes in men treated with currently commercially available bulking agents was performed to determine whether this is a reasonable option in selected patients. Methods The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework of systematic reviews. A comprehensive search of PubMed, Medline, and Embase was undertaken. Abstracts were independently screened by two investigators to include men with stress urinary incontinence treated with a peri-urethral injection of bulking agents currently available in the market. Results Only eight original articles met the inclusion criteria. The bulking agents used were Macroplastique in five studies (total 123 patients), Opsys, Durasphere, and Urolastic in one study each (10, 7, and 2 patients, respectively). Only one study was randomized; Macroplastique vs AUS in men with mild or total incontinence. The included populations were heterogeneous and encompassed endoscopic, perineal, abdominal and laparoscopic prostate surgery as well as spinal cord injuries and urethral sphincter insufficiency. Significant dissimilarity was evident for the duration of incontinence (9-108 months), mean volume of bulking agent used (2.3-13.5 mL), number of cushions (1-5), depth and position of the cushions. The outcomes varied significantly, with reported dry rates between 0% and 83%. Outcomes were limited by relatively short follow-up in most studies. Conclusion Following initial enthusiasm and then dismay with collagen-based compounds, sparse and heterogeneous literature data were produced on newer non-migrating and nonabsorbable bulking agents. Some studies have suggested encouraging, if short term outcomes, however, future studies are needed in this field to support recommendations for widespread use.

AIMS To assess the incidence and management of urodynamic stress urinary incontinence (USUI) in women undergoing transvaginal excision of a urethral diverticulum (UD) at our institution. METHODS A prospective database, capturing patients undergoing urethral diverticulectomy over a 9-year period (May 2007 to August 2016), was reviewed focusing on USUI and subsequent management. RESULTS One hundred patients underwent UD excision (with modified Martius labial fat-pad flap interposition). Preoperative magnetic resonance imaging data, available in 90 patients, demonstrated that 80% had complex diverticula. Complete urodynamic data were available for 93 patients. Preoperatively, 27 patients (29%) had USUI of which 16 patients resolved with either UD excision alone (n = 8) or 3 months of pelvic floor muscle therapy (PFMT) (n = 8). All 11 with persistent postoperative USUI had video urodynamics (VUDs) confirming Blaivas type 3 USUI. Six patients had a rectus fascial pubovaginal sling (RFPVS) with success in five (83.3%) while five had a mid-urethral obturator tape (MUT-O) with 100% success. Sixteen patients developed de novo stress urinary incontinence (SUI) postoperatively, with resolution after PFMT in 12 (75%). VUDS identified USUI (Blaivas type 3) in two (of the remaining four) patients, managed successfully with MUT-O (n = 1) and RFPVS (n = 1). CONCLUSION Preoperative USUI is present in 29% with UD. Postoperatively, 35.5% (n = 33) have pre-existing (19) or de novo (14) SUI, of which 60.6% (n = 20) resolves after 12 months of conservative management. Surgery for USUI is required in 13 (13.9%), with cure in 92.3%. This supports our practice to excise UD primarily and delay USUI surgery, therefore, avoiding overtreatment for the majority.

Objectives To evaluate functional outcomes of surgery in patients with ectopic ureters diagnosed in adulthood; to review the world literature. Patients and methods Patients were referred over 10 years. Data including surgical history, presenting symptoms, diagnostic modalities, interventions and functional outcomes were collected; and the world literature reviewed. Results 9 women and 1 man had a mean age of 37 (range 20-58). All women were referred with lifelong leakage. The man was referred with storage LUTS. Three women had heminephrectomy/nephrectomy with the distal ureter left in-situ prior to referral. MRI was the predominant diagnostic tool but often took senior review to confirm the diagnosis. Excision of the ectopic ureter was performed with bladder neck reconstruction in 6 women, with concomitant rectus fascial sling in one patient. 4 of 6 (67%) women were cured of their stress incontinence with the bladder neck reconstruction alone, whilst two required further intervention. Three women had nephroureterectomy alone as primary treatment of which two were cured. The single male had heminephrectomy and excision of seminal vesicle. Conclusions Ectopic ureter is a rare diagnosis in adults but should be considered in patients who describe lifelong incontinence. Fine slice MRI is the imaging of choice. Excision of the ureter with bladder neck reconstruction alone was successful in two-thirds of patients, whilst further stress urinary incontinence surgery was required in one-third. Malignancy in ureteric remnants is described in 8% of the world literature. Patients should be counselled of this risk if the ureter is left in-situ.

Introduction In the development of terminology of the lower urinary tract, due to its increasing complexity, the terminology for male lower urinary tract and pelvic floor symptoms and dysfunction needs to be updated using a male-specific approach and via a clinically-based consensus report. Methods This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 22 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Results A Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction, encompassing around 390 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in male lower urinary tract and pelvic floor dysfunction. Male-specific imaging (ultrasound, radiology, CT, and MRI) has been a major addition whilst appropriate figures have been included to supplement and help clarify the text. Conclusions A consensus-based Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Aims The complexity of urethral diverticulectomy depends on location, size, and degree of circumferential involvement. MRI features were examined to predict functional outcome after surgery for urethral diverticulum (UD). Methods A prospectively acquired database was of all patients who have had surgical excision of UD at a tertiary center since 2004 was reviewed. Particular focus was pre- and post-operative urodynamically proven stress urinary incontinence (USUI), and pre-operative MRI features. MRI parameters included diverticular volume, degree of circumferential involvement around the urethra, distance of the Os of UD to bladder neck and urethral length. Students t-test and Mann-Whitney U-test were used to compare rates of de novo USUI. Results There were 100 patients (mean age 45.8 yrs), who had excision of UD since 2004, with a minimum follow-up of 10 months (range 10-112 months). Full MRI data was available for 83 patients. Fourteen were of simple configuration (16.8%), 32 were horseshoe (38.6%), and 37 (44.6%) were circumferential. Twenty-five (25%) patients had pre-operative USUI, while 12 (12%) patients developed de novo USUI post-excision. While, the majority of patients with de novo USUI (67%) had >270° circumferential involvement of urethra, the pre-operative diverticular volume did not predict the likelihood of USUI developing (P = 0.3). A shorter urethral length was associated with pre-operative USUI. Conclusions 25% of all patients had pre-op USUI, and diverticular volume and urethral length was significantly smaller in this group. The majority of patients with de novo USUI had complex diverticula configuration with higher baseline circumferential angle around urethra, with 67% of angle's between 270 and 360°.

A 4-year-old girl was referred to the Undiagnosed Diseases Network with a history of short stature, thin and translucent skin, macrocephaly, small hands, and camptodactyly. She had been diagnosed with possible Hallerman-Streiff syndrome. Her evaluation showed that she was mosaic for uniparental isodisomy of chromosome 1, which harbored a pathogenic c.1077dupT variant in ZMPSTE24 which predicts p.(Leu362fsX18). ZMPSTE24 is a zinc metalloproteinase that is involved in processing farnesylated proteins and pathogenic ZMPSTE24 variants cause accumulation of abnormal farnesylated forms of prelamin A. This, in turn, causes a spectrum of disease severity which is based on enzyme activity. The current patient has an intermediate form, which is a genocopy of severe Progeria.

Introduction The terminology for adult neurogenic lower urinary tract dysfunction (ANLUTD) should be defined and organized in a clinically based consensus Report. Methods This Report has been created by a Working Group under the auspices and guidelines of the International Continence Society (ICS) Standardization Steering Committee (SSC) assisted at intervals by external referees. All relevant definitions for ANLUTD were updated on the basis of research over the last 14 years. An extensive process of 18 rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). Results A Terminology Report for ANLUTD, encompassing 97 definitions (42 NEW and 8 CHANGED, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different groups involved not only in lower urinary tract dysfunction but additionally in many other medical specialties. Conclusion A consensus-based Terminology Report for ANLUTD has been produced to aid clinical practice and research.

Objective Bladder outlet obstruction (BOO) in women remains an underdiagnosed condition. Although diagnosed rarely in general urologic practice, its incidence in specialist centers has been reported to be up to 29%. In the present study we evaluated the incidence of female BOO in adult women referred for evaluation of lower urinary tract symptoms or urinary incontinence, assessing its etiology and correlating this with its clinical presentation. Methods The present study consisted of a retrospective review of a prospectively acquired videourodynamic database of 1142 consecutive women referred for evaluation of lower urinary tract symptoms (LUTS) or urinary incontinence from March 2007 to December 2012 and diagnosed with BOO. After exclusions, data from 1014 patients were analyzed. BOO was defined using a combination of radiographic evidence of obstruction during the voiding phase of the urodynamic study and pressure–flow criteria (Solomon–Greenwell nomogram). Diagnosis was confirmed by cystoscopy, maximal urethral closure pressure, and magnetic resonance imaging as clinically indicated. Results In all, 192 women (19%) were diagnosed with BOO. Functional sphincteric obstruction was diagnosed in 70 women (36%). The most common anatomical cause of BOO was previous anti-incontinence surgery, followed by urethral stricture, diagnosed in 21% and 20% of patients, respectively. The most common presenting symptoms were storage phase symptoms of daytime and night-time urinary frequency. Conclusions BOO was present in 19% of women with LUTS. Functional sphincteric obstruction was the most common cause (36%), followed by obstruction after anti-incontinence surgery (21%). The most common presenting symptom was daytime urinary frequency. BOO should be suspected in women with refractory LUTS, especially those presenting with urinary frequency.

As the understanding of the mechanisms that underlie the overactive bladder have increased, so its diagnosis and management have become more complex. This article, based on a consensus group meeting, provides guidance on the current management of overactive bladder in primary care.

Objective To assess the presenting features and medium-term symptomatic outcomes in women having excision of urethral diverticulum with Martius labial fat pad (MLFP) interposition. Patients and Methods We reviewed our prospective database of all female patients having excision of a symptomatic urethral diverticulum between 2007 and 2015. Data on demographics, presenting symptoms and clinical features were collected, as well as postoperative outcomes. Results In all, 70 women with a mean (range) age of 46.5 (24–77) years underwent excision of urethral diverticulum with MLFP interposition. The commonest presenting symptoms were a urethral mass (69%), urethral pain (61%), and dysuria (57%). Pre-existing stress urinary incontinence (SUI) was present in 41% (29) of the women. After surgery, at a mean (SD) of 18.9 (16.4) months follow-up (median 14 months), complete excision of urethral diverticulum was achieved in all the women, with resolution of urethral mass, dysuria and dyspareunia in all, and urethral pain in 81%. Immediately after surgery, 10 (24%) patients reported de novo SUI, which resolved with time and pelvic floor muscle training such that at 12 months only five (12%) reported continued SUI. There was one symptomatic diverticulum recurrence (1.4%). Conclusions The commonest presenting symptom of a female urethral diverticulum is urethral pain followed by dysuria and dyspareunia. Surgical excision with MLFP interposition results in complete resolution of symptoms in most women. The incidence of persistent de novo SUI in an expert high-volume centre is 12%.

Objective To assess the long-term efficacy of polydimethylsiloxane (Macroplastique®) injection (MPI) in the treatment of Mitrofanoff leakage secondary to valve incompetence. Patients and Methods Between 1995 and 2012, the records of 24 consecutive patients who underwent MPI for Mitrofanoff urinary leakage after continent cutaneous urinary diversion (CCUD) surgery were examined. All patients had a valve deemed of sufficient length (>2 cm) to attempt Macroplastique coaptation. Treatment outcomes were divided into three categories based on physician assessment: success (dry), partial success (>50% reduction in incontinence pads) and failure. Success rates were assessed according to the type of reservoir and conduit channel. Results The mean (range) follow-up was 30 (6–96) months. One patient had initial difficulty catheterising, and subsequently required major revision surgery. In all, 12 patients (50%) failed the treatment and subsequently underwent operative revision to the channel. Three patients (12.5%) achieved complete success; one patient had an appendix channel through native bladder and the remaining two had Monti channels through colon. Nine patients (37.5%) had partial success; success rates were higher with appendix channels (four of six) and colonic reservoirs (six of seven) when compared with Monti channels (eight of 18, 44%) and ileal reservoirs (zero of two). Five of the nine patients with partial success eventually required further surgical revision for deteriorating continence at a mean (range) of 41 (14–96) months, whilst the other four have maintained sufficient continence with MPI alone. Conclusion Macroplastique bulking cured only 12.5% patients, but leakage was substantially improved in a further 37.5% allowing major surgery to be avoided or postponed in one half of the cohort. Appendix Mitrofanoffs do better than the Monti Mitrofanoff, with channels through colonic segments generally doing better than those through ileal bladders. MPI should be considered as a less invasive alternative to avoid or delay major reconstructive surgery.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose homeostasis. We hypothesized that analysis of the entire metabolome in PAH would reveal multiple other metabolic changes relevant to disease pathogenesis and possible treatment. Layered transcriptomic and metabolomic analyses of human pulmonary microvascular endothelial cells (hPMVEC) expressing two different disease-causing mutations in the bone morphogenetic protein receptor type 2 (BMPR2) confirmed previously described increases in aerobic glycolysis but also uncovered significant upregulation of the pentose phosphate pathway, increases in nucleotide salvage and polyamine biosynthesis pathways, decreases in carnitine and fatty acid oxidation pathways, and major impairment of the tricarboxylic acid (TCA) cycle and failure of anaplerosis. As a proof of principle, we focused on the TCA cycle, predicting that isocitrate dehydrogenase (IDH) activity would be altered in PAH, and then demonstrating increased IDH activity not only in cultured hPMVEC expressing mutant BMPR2 but also in the serum of PAH patients. These results suggest that widespread metabolic changes are an important part of PAH pathogenesis, and that simultaneous identification and targeting of the multiple involved pathways may be a more fruitful therapeutic approach than targeting of any one individual pathway.

High-altitude pulmonary hypertension (HAPH) is a consequence of chronic alveolar hypoxia, leading to hypoxic vasoconstriction and remodeling of the pulmonary circulation. Brisket disease in cattle is a naturally occurring animal model of hypoxic pulmonary hypertension. Genetically susceptible cattle develop severe pulmonary hypertension and right heart failure at altitudes >7,000 ft. No information currently exists regarding the identity of the pathways and gene(s) responsible for HAPH or influencing severity. We hypothesized that initial insights into the pathogenesis of the disease could be discovered by a strategy of (1) sequencing of functional candidates revealed by single nucleotide polymorphism (SNP) analysis and (2) gene expression profiling of affected cattle compared with altitude-matched normal controls, with gene set enrichment analysis (GSEA) and Ingenuity pathway analysis (IPA). We isolated blood from a single herd of Black Angus cattle of both genders, aged 12-18 months, by jugular vein puncture. Mean pulmonary arterial pressures were 85.6±13 mmHg STD in the 10 affected and 35.3±1.2 mmHg STD in the 10 resistant cattle, P

To report the long-term outcomes of augmentation ileocystoplasty (AIC) in patients with spinal cord injury (SCI), with a minimum follow-up period of 10 years.

OBJECTIVETo compare the effect of repeated detrusor injections of botulinum toxin (BoNT-A) on health-related quality of life (HRQL) in patients with idiopathic (IDO) or neurogenic detrusor overactivity (NDO).PATIENTS AND METHODSBetween 2003 and 2009, 151 patients (109 with NDO and 42 with IDO) were treated by BoNT-A (Botox (R), Allergan Inc., Irvine, CA, USA). Changes in HRQL were assessed using the validated short forms of Urogenital Distress Inventory (UDI-6), the Incontinence Impact Questionnaire (IIQ-7) and EuroQOL-5D (EQ-5D) before and 4 weeks after BoNT-A.RESULTSThe maximum number of repeated injections was five (mean +/- SD, 2.8 +/- 1.05). Mean +/- SD follow-up was 27.49 +/- 17.01 months.The UDI-6 and IIQ-7 questionnaires showed a consistent improvement after repeated injections in both groups with detrusor overactivity. The EQ-5D was not statistically different before and after each injection in either the NDO or IDO population.After repeated injections, no statistical differences in the change on the UDI-6 and IIQ-7 scores were found between NDO and IDO, except after the first treatment, when the decrease in UDI-6 was higher in NDO than in IDO.The EQ-5D anxiety and depression subscore improved in both groups after each injection and with the number of injections.In IDO, after the second injection, no patient reported extreme anxiety or depression and, after the fourth injection, none had anxiety or depression.The inter-injection interval was shorter after the first injection in those with NDO than in IDO but was similar thereafter.CONCLUSIONSIntradetrusor injections of BoNT-A improved the HRQL of both NDO and IDO patients.Although improvement in HRQL was greater and the duration of efficacy shorter in NDO patients after the first injection, there was no significant difference after subsequent injections.Mean inter-injection interval in IDO and in NDO patients was similar from the second injection onwards and improvements in HRQL score were the same.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To evaluate the long-term safety and efficacy of the tension-free vaginal tape (TVT) for the treatment of stress urinary incontinence (SUI) in women with neuropathic bladder dysfunction. PATIENTS AND METHODS Twelve women (mean age 53.3 years, range 41–80) with neuropathic bladder dysfunction and SUI confirmed by video-cystometrography (VCMG) were treated with a TVT in one institution by an expert neuro-urologist between November 1997 and December 2000. The patient’s notes, clinical annual follow-up and VCMG after the procedure, and the incontinence impact questionnaire (IIQ) forms (Urinary Distress Inventory, and IIQ-7) were assessed during the long-term clinical follow-up for SUI, in addition to a health-related quality of life assessment. The cure of SUI was defined as no loss of urine on physical exercise, confirmed VCMG after the procedure, and by clinical assessment. RESULTS The mean (range) follow-up was 10 (8.5–12) years. Nine patients were using clean intermittent self-catheterization before the insertion of TVT and continued to do so afterward. At 10 years of follow-up, one patient had died (with failed TVT initially), and two were lost to follow-up at 5 years after surgery, but up to 5 years they did not complain of UI and VCMG did not show SUI. The remaining seven of the nine patients were completely dry, and two improved and were satisfied with using one or two pads/day. Two patients showed neurogenic detrusor overactivity confirmed on VCMG, with no evidence of SUI. One patient needed a transient urethral catheter for urinary retention after surgery, one had a bladder injury that required leaving the catheter for 5 days, but no urethral erosions were reported during the follow-up. CONCLUSIONS In women with neuropathic bladder dysfunction secondary to a variety of spinal cord pathologies, and who have SUI necessitating a definitive intervention, insertion of TVT should be considered a desirable treatment, with very good long-term outcomes.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To assess the long-term (20 years) effectiveness of the UroLume wallstentTM (Pfizer Inc., UK) in the treatment of detrusor external sphincter dyssynergia (DESD) in patients with spinal cord injury (SCI). PATIENTS AND METHODS Twelve patients with quadriplegia secondary to SCI underwent external striated sphincter stenting with the UroLume wallstent in place of sphincterotomy for DESD ≈ 20 years ago. The mean (range) age was 41.8 (26–65) years. Eleven patients had cervical level injury whilst one had a thoracic injury. All the patients were shown to have high-pressure neurogenic detrusor overactivity and DESD with incomplete emptying on preoperative video-cystometrograms (VCMG). RESULTS Six of the 12 patients have now been followed-up for a mean (range) of 20 (19–21) years. Of the remaining six, two were lost to follow-up at 1 and 3 years, but both remained free of complications during that time. Two patients developed encrustation causing obstruction, requiring stent removal within 1 year of insertion. Another patient with an adequately functioning stent died 7 years after stent insertion from a chest infection. The twelfth patient developed bladder cancer 14 years after stent insertion and underwent cystectomy with urinary diversion. VCMG follow-up of the six patients showed a significantly sustained reduction of maximum detrusor pressure and duration of detrusor contraction at the 20-year follow-up. Five of these six patients developed bladder neck dyssynergia of varying degrees as shown on VCMG within the first 9 years of follow-up. All were successfully treated with bladder neck incision (BNI) where the last BNI needed was at 12 years. We did not encounter any problem with stent migration, urethral erosion, erectile dysfunction or autonomic dysreflexia. CONCLUSION Urethral stenting using the UroLume wallstent is effective in the management of DESD in patients with SCI and provides an acceptable long-term (20-year follow-up) alternative to sphincterotomy. The failures manifest within the first few years and can be managed easily with stent removal without any significant problems. Bladder neck dyssynergia was the long-term complication which was treated successfully with BNI. It has no significant interference with erectile function, being reversible, minimally invasive and has a shorter hospital stay.

Bone morphogenetic protein receptor type 2 (BMPR2 ) gene mutations are a major risk factor for heritable pulmonary arterial hypertension (HPAH), an autosomal dominant fatal disease. We have previously shown that BMPR2 transcripts that contain premature termination codon (PTC) mutations are rapidly and nearly completely degraded through nonsense mediated decay (NMD). Here we report a unique PTC mutation (W13X) that did not behave in the predicted manner. We found that patient-derived cultured lymphocytes (CLs) contained readily detectable levels of the PTC-containing transcript. Further analysis suggested that this transcript escaped NMD by translational re-initiation at a downstream Kozak sequence, resulting in the omission of 173 amino acids. Treatment of CLs containing the PTC with an aminoglycoside decreased the truncated protein levels, with a reciprocal increase in full-length BMPR2 protein and, importantly, BMPR-II signaling. This is the first demonstration of aminoglycoside-mediated ‘repair’ of a BMPR2 mutation at the protein level in patient-derived cells and has obvious implications for treatment of HPAH where no disease-specific treatment options are available. Our data also suggest the need for a more thorough characterization of mutations prior to labeling them as haploinsufficient or dominant negative based simply on sequencing data.

OBJECTIVETo evaluate screening cystoscopy as the long-term follow up in patients with an enterocystoplasty for >= 10 years.PATIENTS AND METHODSWe performed a prospective analysis of 92 consecutive patients who attended our endoscopy suite for regular check cystoscopy as per standard follow-up. This is performed for all patients with cystoplasty performed at our institute after 10 years. The data were recorded on patient demographics, original diagnosis and type of cystoplasty. In all, 53 of these patients consented to undergo bladder biopsies at the same time.RESULTSThe median (range) follow-up was 15 (10-33) years. No cancer was identified with either surveillance cystoscopy or on routine biopsies. Chronic inflammation was identified in 25 biopsies (27%). Villous atrophy was present in 12 (55%) ileal patch and three (12.5%) colonic patch biopsies. During this study, the first and only case of malignancy in a cystoplasty at our institution was diagnosed in a symptomatic patient. She had intermittent haematuria and recurrent urinary tract infections (UTIs). She previously had a normal surveillance cystoscopy.CONCLUSIONSWe feel that it is not necessary to perform yearly check cystoscopies in patients with augmented bladders at least in the first 15 years, as cancer has not yet been detected with surveillance cystoscopy in this patient group. However, if the patient develops haematuria or other worrisome symptoms including suprapubic pain and recurrent unexplained UTIs a full evaluation, including cystoscopy and computerized tomography should be undertaken.

Transforming growth-interacting factor (TGIF) is a homeobox transcriptional repressor that has been implicated in holoprosencephaly and various types of cancer. TGIF is expressed in hematopoietic stem cells and modulates TGF-beta and retinoic acid (RA) signaling, both of which play an important role in hematopoiesis. We recently reported that TGIF's levels correlate inversely with survival in patients with acute myelogenous leukemia. Here we present the first direct evidence of a role for TGIF in myelopoiesis. We used short hairpin RNA interference to define the effects of TGIF knockdown on proliferation and differentiation of myeloid leukemia-derived cell lines. Decreased TGIF expression resulted in reduced proliferation and differentiation and lower expression of CEBPbeta, CEBPepsilon, PU.1 and RUNX1, key myeloid transcription factors. Furthermore, TGF-beta signaling was increased and RA signaling was decreased. Further insights into the molecular basis of TGIF's effects were provided by a genome-wide chromatin immunoprecipitation-based elucidation of TGIF target genes. Together, these data suggest that TGIF has an important role myelopoiesis and may regulate the balance between proliferation and differentiation. Reduced TGIF expression could tip the balance toward quiescence thus providing progenitor as well as hematopoietic stem cells protection from anti-cycle agents.

OBJECTIVE: To present our experience with the use of injectable polydimethylsiloxane (Macroplastique, Uroplasty, Minneapolis, MI, USA) for treating incontinence in children with the exstrophy-epispadias complex (EEC), as incontinence continues to be a challenging problem in such children, and although the primary management of EEC has developed over the last few decades, with early closure and reconstruction of the penis, achieving satisfactory continence status remains elusive. PATIENTS AND METHODS: We retrospectively reviewed the hospital records of 52 patients (41 boys and 11 girls, mean age at first injection 6.6 years, range 3.6-16.7) with EEC who had injections with Macroplastique between January 1991 and February 2004; 34 had bladder exstrophy and 18 primary epispadias. For this study we defined success as complete dryness with no use of pads or nappies. Improvement was defined as being occasionally wet but with dry intervals lasting >or= 4 h. RESULTS: The mean (range) follow-up was 4.6 (0.5-9) years. Twenty patients had one injection, 10 had two, 13 had three, six had four, two had six and one had seven injections. In most patients a maximum of three injections predicted the outcome. The injection of Macroplastique was successful in nine patients (17%; with an annual follow-up, two at 1-2 years, three at 2-5 years and four at >5 years), whilst 17 (33%) improved significantly (one at 5 years). Those patients comprised five of 18 (27%) with epispadias and four of 34 (12%) with exstrophy. A history of previous surgery and gender had no significant effect on the outcome. Overall half the patients benefited from the procedure. CONCLUSIONS: This series confirms that injection with Macroplastique is minimally invasive, durable in significantly many patients and has a reasonable success rate. A history of previous surgery and gender had no significant effect on the outcome. Patients with epispadias are more likely to benefit from an injection with Macroplastique than those with bladder exstrophy. A maximum of three injections is predictive with reasonable certainty of any benefit from the procedure

We describe identical twin sisters born to nonconsanguineous, healthy parents. Both twins had situs viscerum inversus and developed hypertrophic cardiomyopathy in adulthood. Am. J. Med. Genet. 91:327–330, 2000. © 2000 Wiley-Liss, Inc.

The RUNOFF block of EPA's storm water management model (SWMM) was used to simulate the quantity and quality of urban storm water runoff from four relatively small sites (i.e. 5·97–23·56 ha) in South Florida, each with a specific predominant land use (i.e. low density residential, high density residential, highway and commercial). The objectives of the study were to test the applicability of this model in small subtropical urban catchments and provide modellers with a way to select appropriate input parameters to be used in planning studies. A total of 58 storm events, measured by the US Geological Survey (USGS), provided hyetographs, hydrographs and pollutant loadings for biological oxygen demand (BOD5), total suspended solids (TSS), total Kjeldahl nitrogen (TKN) and lead (Pb), and were used for calibration of the model. Several other catchment characteristics, also measured or estimated by USGS, were used in model input preparation. Application of the model was done using the Green–Ampt equation for infiltration loss computation, a pollutant accumulation equation using a power build-up equation dependent on the number of dry days, and a power wash-off equation dependent on the predicted runoff rate. Calibrated quantity input parameters are presented and compared with suggested values in the literature. The impervious depression storage was generally found to be the most sensitive calibration parameter, followed by the Manning's roughness coefficients of conduit and overland flow, the Green–Ampt infiltration parameters and, finally, the pervious depression storage. Calibrated quality input parameters are presented in the form of regression equations, as a function of rainfall depth and the number of antecedent dry days. A total of 16 independent rainfall events were used for verification of the model, which showed a good comparison with observed data for both hydrographs and pollutant loadings. Average model predictions for the four constituent concentrations from the verification runs also showed good agreement with NURP published values in Florida and US sites. © 1998 John Wiley & Sons, Ltd.

Runoff depth and pollutant loading (Biological Oxygen Demand [BOD5], Total Suspended Solids [TSS], Total Kjeldahl Nitrogen [TKN] and lead [Pb]) computations of urban stormwater runoff from four small sites (i.e., 14.7–58.3 ac) in South Florida were performed using the Soil Conservation Service (SCS) hydrology method and empirical equations developed by the U.S. Environmental Protection Agency (EPA). Each site had different predominant land uses (i.e., low density residential, high density residential, highway and commercial). Quantity and quality data from 95 storm events at these sites were measured by the U.S. Geological Survey (USGS), and used for calibration of the methodology to derive appropriate input parameters. Calibrated input parameters were developed for each land use to test the applicability of the methodology in small sub-tropical urban watersheds, and to provide hydrologists with a way to select appropriate parameter values for planning studies. A total of 16 independent rainfall events were used for verification of the methodology. Comparisons of predicted versus measured data for both hydrographs and pollutant loadings were performed.

Introduction: We evaluated safety and long-term efficacy of TVT in treatment of urodynamic stress incontinence (USI) in females with neuropathic bladders. Method: Sixteen incontinent female patients were treated. 11 women were postlumbar spinal surgery and five postspinal cord injury. Four had previously failed surgery for USI. Patient demographics, pre and postoperative clinical and videocystometrogram (VCMG) parameters were recorded. Continence assessment at 6 weeks (voiding diary and pad test), 3 months (VCMG) and yearly follow up was recorded. Results: Mean age was 55 years with mean follow up of 52.7 months (range 12–86). At last follow up 87.5% patients (14/16) were continent. The two failures were due to persistent USI and postoperative detrusor hyperreflexia (DH). DH was pre operatively present in 4, requiring simultaneous intra detrusor botulinum toxin injections in two and anticholinergic medications in rest. Bladder perforation was seen in one and urinary infections in three. Mean pre and postoperative detrusor pressures were 23.8 and 15 cm of water. Two patients continued to use pads (3/day) similar to pre operative cumulative average of three pads/day. Preoperatively 11 patients performed intermittent catheters (SIC), three spontaneous voids (SV) and one combination of the two with one on indwelling urethral catheter (IDUC). One patient each on SV, SIC and IDUC changed to SIC. Conversely one each on SIC and SV changed to combination. Conclusion: TVT is safe, effective long-term treatment for USI in females with neuropathic bladders. DH needs adequate suppression with regular VCMG follow up. Previous incontinence surgery did not affect complications or outcome.