Fallacies of clinical studies on folic acid hazards in subjects with a low vitamin B12 status.

A 2016 plea for revision of the 1 mg/day upper level of folic acid intake prompted us to comprehensively review the 1945-2017 literature on folic acid hazards in subjects with low cyanocobalamin. The concept of folic acid treatment 'masking' the anemia in undiagnosed cyanocobalamin deficiency, thereby delaying the diagnosis of neuropathy, does not account for the dissociation between the deficiency's hematologic and neurologic manifestations. Possible risks of this concept were addressed by 1963-1971 FDA rulings, classifying all folic acid preparations as prescription-only drugs, delivering ≤1 mg daily. The neuropathy in folic acid trials for 'pernicious anemia' is due to the singular use of folic acid-neuropathy improved or disappeared with replacement of folic acid by liver extract or cyanocobalamin. The hypothesis that cognitive impairment in 'subclinical' cyanocobalamin deficiency is folate-mediated is untenable. Of 6 papers specifically investigating this, none could prove that increased cognitive impairment was related to high folate intake. This review fully supports the safety of the 1 mg/day upper level for folic acid intake.

Visual rehabilitation of patients with corneal diseases.

BACKGROUND: Although most patients with visual impairment due to corneal diseases can be treated successfully with surgery, some require visual rehabilitation to restore reading ability. To evaluate the best LVAs especially in terms of reading speed and characterize this specific patient group we performed a prospective, randomized cross-over trial. METHODS: All 34 patients underwent a detailed examination (slit-lamp, funduscopy, SD-OCT, ETDRS) as screening. Only patients with corneal diseases without other ocular diseases were included. Reading-speed was assessed with International-Reading-Speed-Texts (IReST) consecutively with five different LVAs (low vision aids) during one day in a randomized cross-over design. Corneal haze was quantified with corneal densitometry (Pentacam). RESULTS: Patients were either visually impaired (n = 28), severely impaired (n = 4) or legally blind (n = 2). Patients read significantly faster with LVAs (p < 0.0001). Fastest reading speed could be achieved with video magnifier (CCTV). Optical magnifier and portable-electronic magnifier enabled significantly lower reading speeds (p < 0.01). In a subgroup of patients (VA < 3/60,n = 6) black background enabled patients to read significantly faster compared to white background (p = 0.03). CONCLUSION: Patients with low magnification requirement can be treated successfully with optical LVAs and portable-electronic magnifiers. More severely afflicted patients need a CCTV. Black background enables fastest reading-speeds, probably due to less blinding. Visual impairment can be estimated with corneal densitometry. Our trial confirms the capability of LVAs to successfully restore the reading ability in patients with corneal diseases, which is a crucial part of visual rehabilitation. TRIAL REGISTRATION: This trial was registered at the German Clinical Trials Register as DRKS00010887 at 09.08.2016.

Diagnosis and Empirical Treatment of Urinary Tract Infections in Urologic Outpatients.

INTRODUCTION: Due to a continuing increase of bacterial resistance in common uropathogens, we wanted to revisit our standards for the diagnosis and treatment of lower urinary tract infections, in the setting of urological outpatient care in a conurbation in Germany. PATIENTS AND METHODS: All subjects presenting with significant bacteriuria at our urology clinics in Mülheim, Germany, in 2011 were included. Comorbidity, bacterial species, urinary tract symptoms, and empirically prescribed antibiotics were taken from the patients' records. RESULTS: In 2011, a total of 1,324 patients were included (793 female, 531 male). Of the 771 patients with symptomatic bacteriuria, 647 received antibiotic treatment, as well as 116 of 409 patients with asymptomatic bacteriuria. Escherichia coli was identified in 60% of the included patients. In 427 E. coli infections, bacterial resistance was found in 14% of 316 cases treated with quinolone, in 21% of 53 cases treated with co-trimoxazole, and in only 3% of 58 cases treated with nitrofurantoin. CONCLUSIONS: We found a high use of fluoroquinolones for empirical first-line antibiotics in the treatment of lower urinary tract infections. In our regional setting, antibiotic stewardship needs to be promoted, along national and international guidelines, to avoid unnecessary prescription of fluoroquinolones for empirical treatment.

Long-term outcome of intravesical oxybutynin in children with detrusor-sphincter dyssynergia: with special reference to age-dependent parameters.

AIMS: Intravesical instillation of oxybutynin is an accepted and effective treatment in children with neuropathic bladder-sphincter dysfunction, when oral oxybutynin results in inadequate suppression of detrusor overactivity or intolerable side effects. However, as yet no data are available on long-term use and outcome. METHODS: A patient cohort with detrusor-sphincter dyssynergia that started oral oxybutynin between 1995 and 1997 was re-evaluated 15 ± 1 years after the switch from oral to intravesical (n = 10), with urodynamic investigations, renal ultrasounds, DMSA-scintigraphy, (51)Cr-EDTA-clearance, and validated questionnaires on incontinence and quality of life. RESULTS: At follow-up, cystometric bladder capacity (CBC) had increased to the 25-50% percentiles for age, from the 5% percentile; mean end-filling pressure, 24.5 ± 14.4 cm H2O, had returned to the safe zone; bladder compliance expressed as a fraction of normal compliance for age (Wahl units) showed a statistically significant increase. At follow-up, the prevalence of renal scars was 30% (95% CI: 6-65%). Kidney lengths correlated with scarring at DMSA-scintigraphy, (51)Cr-EDTA-clearance did not. In 2 years of oral oxybutynin we documented 10 pyelonephritic episodes, in 15 years of intravesical oxybutynin only three. Urinary continence was reported as satisfying, its impact on quality of life as acceptable. CONCLUSION: Percentile charts for cystometric bladder capacity and individual kidney lengths, age-dependent parameters, were invaluable in estimating long-term outcome, and the same goes for bladder compliance in Wahl units. We can conclude that intravesical oxybutynin provided more than adequate suppression of detrusor activity, without side effects, over a period of 15 years.

Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence.

OBJECTIVE: Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. METHODS: Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. RESULTS: In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. CONCLUSION: The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways.

Investigator bias in urodynamic studies for functional urinary incontinence.

PURPOSE: In the setting of the European Bladder Dysfunction Study, a multicenter, randomized, controlled trial of treatment options for functional incontinence in children, we assessed the concordance between reported and reviewed urodynamic scores. MATERIALS AND METHODS: A total of 97 children with clinically diagnosed urge syndrome and 105 with clinically diagnosed dysfunctional voiding enrolled in the European Bladder Dysfunction Study and underwent full urodynamic studies before and immediately after treatment for urinary incontinence. Photocopies of 72% of the original urodynamic recordings were available for blinded review. RESULTS: The concordance for detrusor overactivity throughout the filling phase was 37% in urge syndrome cases and for increased pelvic floor activity during voiding it was 81% in dysfunctional voiding cases. Differences in original and reviewed scores were equally distributed among participating centers. CONCLUSIONS: Concordance between original and reviewed urodynamic scores was low for detrusor overactivity. Concordance was acceptable for increased pelvic floor activity during voiding but was not specific for dysfunctional voiding. Since interpreting urodynamic studies is based on pattern recognition, investigator bias can only be compensated for by blinded review of the actual recordings.

Improving the cure rate of alarm treatment for monosymptomatic nocturnal enuresis by increasing bladder capacity--a randomized controlled trial in children.

PURPOSE: We prospectively assessed response and cure rates of alarm treatment, following pretreatment with antimuscarinics and/or holding exercises aimed at increasing maximum volume voided in 149 children with monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: In a prior trial the same 149 children had been randomized into 5 groups to assess interventions for increasing maximum volume voided, namely placebo or antimuscarinics with (groups A and B, respectively) and without (C and D, respectively) holding exercises, and a control group (E) receiving just alarm treatment. Following pretreatment groups A to D received alarm treatment. Full response and cure rates were assessed, as well as the influence on these rates of baseline maximum volume voided, increase in maximum volume voided after pretreatment, gender, age and previous treatment. RESULTS: Neither full response nor cure was influenced significantly by the increase in maximum volume voided achieved in groups A and B with holding exercises. Overall full response ranged from 50% to 73%, and overall cure ranged from 50% to 67%. Possible predictors for full response and cure were prior treatment (p <0.02) and age younger than 8 years (p <0.05). CONCLUSIONS: In monosymptomatic nocturnal enuresis increasing maximum volume voided does not affect response or cure rate of subsequent alarm treatment. Previous treatment and age younger than 8 years are possible predictors for response and cure.

The relevance of urodynamic studies for Urge syndrome and dysfunctional voiding: a multicenter controlled trial in children.

PURPOSE: The objective of this study was to compare prospectively, in urge syndrome and dysfunctional voiding, clinical patterns with urodynamic patterns, to assess changes in urodynamic patterns after treatment, and to correlate urodynamic patterns and parameters with treatment outcome. MATERIALS AND METHODS: In the European Bladder Dysfunction Study 97 children with clinically diagnosed urge syndrome received standard treatment, to which was randomly added placebo, oxybutynin or bladder training with online feedback. In a separate branch 105 children with clinically diagnosed dysfunctional voiding were randomly allocated to standard treatment or standard treatment plus pelvic floor training with online feedback. In all children urodynamic studies were performed before and immediately after treatment. RESULTS: In urge syndrome detrusor overactivity was present in 33% of cases before and 27% after treatment (of which 65% were de novo). Detrusor overactivity did not correlate with treatment outcome. In dysfunctional voiding increased pelvic floor activity during voiding, which was present in 67% of cases before and 56% after treatment (of which 45% were de novo), did not correlate with treatment outcome. In urge syndrome as well as in dysfunctional voiding neither maximum detrusor pressure during voiding, cystometric bladder capacity, bladder compliance nor free flow patterns correlated with treatment outcome. CONCLUSIONS: Neither detrusor overactivity nor increased pelvic floor activity during voiding correlated with treatment outcome. Standard treatment could be the first choice in urge syndrome as well as in dysfunctional voiding, reserving urodynamic studies for patients in whom this first approach fails.

Folic acid and primary prevention of neural tube defects: A review.

With 4 mg folic acid daily, it may take 20 weeks to reach red-blood-cell folate levels between 1050 and 1340 nmol/L, optimal for reduction of the neural tube defect risk. Therefore, folic acid supplementation should be started 5-6 months before conception. The residual risk with optimal red-blood-cell folate levels is reportedly 4.5 per 10,000 total births. The residual risk in pooled data from countries with mandatory folic acid fortification is 7.5 per 10,000 pregnancies, regardless of pre-fortification rates. European monitoring of folate intake with questionnaires should be replaced by periodic measurements of red-blood-cell folate. The risk of folate intake >1 mg/day does not outweigh the benefits of folic acid fortification, provided un-metabolized folic acid, RBC folate and vitamin B12 are monitored periodically. A European monitoring system, based on U.S. National Health and Nutrition Examination Surveys, should reside with the European Centre for Disease Prevention and Control.

Tendon Elongation with Bovine Pericardium in Patients with Severe Esotropia after Decompression in Graves' Orbitopathy-efficacy and Long-term Stability.

BACKGROUND/AIMS: We performed a retrospective analysis to examine clinical results, establish a dose-effect coefficient and analyze the long-term efficacy of tendon elongation with bovine pericardium (Tutopatch®) for surgical correction of severe esotropia, occurring after three-wall orbital decompression for dysthyroid optic neuropathy in patients with Graves' orbitopathy (GO). METHODS: Tendon elongation of the medial rectus muscle (MR) was performed in our institution using an interponate of bovine pericardium in 60 patients (27 underwent unilateral and 33 bilateral surgery). Success-rate (total horizontal deviation of 10 prism-diopters (PD) or less and evidence of binocular single vision with or without prism glasses) and horizontal motility were examined 3 months, 1 and >4 years after surgery. A dose-effect coefficient for deviation reduction (PD) per recession distance (mm) was established. RESULTS: Horizontal deviations between 28-80Δ were corrected. Diplopia in primary-gaze disappeared in 65% of the patients after 3 months and in 83% after one year (including 12 patients who underwent subsequent surgery after 3-month follow-up). Patients with deviations ≤40Δ after unilateral and ≤50Δ after bilateral tendon elongation showed higher primary success-rates after 3 months (78% and 72%). Vertical deviations (≤10Δ) were corrected by the procedure in 28% without need of recession of the inferior rectus (IR). Only 3 patients showed overcorrection after one year. One of these underwent revision surgery, in which the interponate was no longer discernible from surrounding fibrotic scar tissue. At >4-year follow-up (4.3-15years) effects were stable and 95% of patients showed fusion in primary gaze. Median dose-effect coefficient was lower after tendon elongation (1.8Δ/mm) compared to conventional medial rectus recession in patients with GO. Horizontal motility was slightly decreased, but much more symmetric around primary gaze. CONCLUSION: Tendon elongation with a bovine pericardium implant is a safe surgical method, suitable to correct severe esotropia after decompression surgery. A lower dose-effect has to be taken into account. Patients with esotropia ≥42Δ should not be treated with unilateral, but bilateral tendon elongation, to avoid undercorrections. In patients with deviations ≥52Δ it has to be further investigated if the application of even higher elongation distances is viable or if another approach-the recession of more than one rectus muscle has to be performed simultaneously to handle the severe restriction. Generally, a step-by-step approach is advisable, since small vertical deviations could also be corrected in a third of patients with the procedure and the dose-effect was more variable as in medial recessions without tendon elongation.

Urine output rate and maximum volume voided in school-age children with and without nocturnal enuresis.

OBJECTIVE: To compare urine volumes voided and output rates in prepubertal children with and without monosymptomatic nocturnal enuresis (MNE), to investigate the balance between nocturnal urine output and functional bladder capacity. STUDY DESIGN: In 76 prepubertal children with MNE, all voidings were collected over 48 hours: bedwetting volume (BWV), early-morning voiding after a dry night (EMV), and other voided volumes (VV). Output rates were calculated based on volumes voided and time intervals. Data collected in 50 typical prepubertal children were used for comparison. In both populations, holding-exercise volumes (HEV) were also collected, to approximate maximum volume voided (MVV). RESULTS: Of the 15% total bedwetting events recorded with output rates more than 2 standard deviations above the normal population average, only half met the International Children's Continence Society criteria for "nocturnal polyuria." The circadian rhythm of urine output is the same in both populations; during inactivity, low rates and long filling times result in large EMV. BWVs are also produced with low rates, but have shorter filling times. MVV is small for age in MNE, but HEV for age is the same in both populations. Treating MNE with holding exercises needs to be studied prospectively. CONCLUSIONS: The cause of bedwetting might be aborted bladder filling in the circadian inactivity phase rather than nocturnal polyuria.

Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle.

BACKGROUND: In view of consistently high cardiovascular morbidity and mortality rates, international efforts are aimed at developing tools for more precise risk prediction to allow preventive treatment targeted at high-risk individuals. Direct visualization of anatomic, preclinical atherosclerotic disease has the potential for individualized risk discrimination. Further, a variety of risk factors are actively evaluated, including markers of the activity of atherosclerotic disease, thrombogenic risk, and genetic polymorphisms. METHODS: The Heinz Nixdorf RECALL (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study is a population-based, prospective cohort study of the comparative value of modern risk stratification techniques for "hard" cardiac events. It is designed and powered to define the relative risk associated with the specific extent of coronary atherosclerosis measured by means of electron-beam computed tomography (EBCT)-derived coronary calcium quantities for myocardial infarction and cardiac death in 5 years in 4200 males and females aged 45 to 75 years in an unselected urban population from the large, heavily industrialized Ruhr area. Additionally, the predictive values of conventional cardiovascular risk factors, new candidate and socioeconomic risk factors, certain genetic polymorphisms, and direct signs of subclinical disease are examined with the ankle-brachial index, resting and stress electrocardiograms, and determination of carotid artery intima-media thickness. Prospective clinical risk-benefit and health economic analyses are an inherent part of the study. Study findings with established clinical significance are reported to the participants, but the EBCT findings are withheld until the conclusion of the study. CONCLUSIONS: The Heinz Nixdorf RECALL study will define appropriate methods for identifying high-risk subgroups in the general urban population who may derive the greatest benefit from preventive treatment.

Relapse of Graves' disease after successful outcome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine.

Antithyroid drugs are effective in restoring euthyroidism in Graves' disease, but many patients experience relapse after withdrawal. Prevention of recurrence would therefore be a desirable goal. In a prospective study, patients with successful outcome of 12 to 15 months antithyroid drug therapy were stratified for risk factors and randomly assigned to receive levothyroxine in a variable thyrotropin (TSH)-suppressive dose for 2 years or no treatment. The levothyroxine group was randomized to continue or discontinue levothyroxine after 1 year. End points included relapse of overt hyperthyroidism. Of 346 patients with Graves' disease enrolled 225 were euthyroid 4 weeks after antithyroid drug withdrawal and were randomly assigned to receive levothyroxine (114 patients) or no treatment (controls, 111 patients). Of those not randomized, 39 patients showed early relapse within 4 weeks, 61 endogenous TSH suppression, 7 TSH elevation, and 14 had to be excluded. Dropout rate during the study were 13.3%. Kaplan-Meier analyses showed relapse rates to be similar in the levothyroxine group (20% after 1 year, 32% after 2 years) and the randomized controls (18%, 24%), whereas relapses were significantly more frequent in the follow-up group of patients with endogenously suppressed TSH (33%, 49%). Levothyroxine therapy did not influence TSH-receptor antibody, nor did it reduce goiter size. The best prognostic marker available was basal TSH determined 4 weeks after withdrawal of antithyroid drugs (posttreatment TSH). The study demonstrates that levothyroxine does not prevent relapse of hyperthyroidism after successful restoration of euthyroid function by antithyroid drugs and characterizes posttreatment TSH as a main prognostic marker.

Ultrasound evaluation of mediastinal lymphadenopathy in patients with sarcoidosis.

AIM: Mediastinal lymphadenopathy is a typical feature of pulmonary sarcoidosis and an important parameter for diagnosis and follow-up. The present feasibility study is the first to elucidate the role of transthoracic mediastinal ultrasonography (US) for evaluation and staging of lymphadenopathy in patients with sarcoidosis. MATERIAL AND METHOD: Fifty patients with sarcoidosis were subjected to high-definition mediastinal US. The sonographic lymph node status was compared with the radiologic staging - the prevailing gold standard. RESULTS: Mediastinal regions and landmarks could reliably be assessed by ultrasound in 45/50 (90%) of sarcoidosis patients. Lymphadenopathy was sonographically documented in 29/50 (58%) of the patients (sensitivity 89%, specificity 76%, PPV 86%, NPV 81%, accuracy 84%). There was a marked concordance between US confirmation of lymphadenopathy and radiologic staging (k=0.67, p<0.001). CONCLUSIONS: Transthoracic US qualifies for the demonstration of the mediastinal regions and lymphadenopathy in patients with sarcoidosis. The procedure is facilitated by frequent and distinct mediastinal lymph node enlargement due to sarcoidosis. Prospective studies are required to find out whether mediastinal US adds value to conventional radiologic staging and provides a clinically advantage, particularly in the follow-up of patients with sarcoidosis.

Behavior profiles in children with functional urinary incontinence before and after incontinence treatment.

OBJECTIVE: The purpose of this work was to analyze prospectively the prevalence of behavioral disorders in children with urinary incontinence because of nonneuropathic bladder-sphincter dysfunction before and after treatment for incontinence. METHODS: A total of 202 children with nonneuropathic bladder-sphincter dysfunction were enrolled in the European Bladder Dysfunction Study, in branches for urge syndrome (branch 1) and dysfunctional voiding (branch 2); 188 filled out Achenbach's Child Behavior Checklist before treatment and 111 after treatment. Child Behavior Checklist scales for total behavior problems were used along with subscales for externalizing problems and internalizing problems. RESULTS: After European Bladder Dysfunction Study treatment, the total behavior problem score dropped from 19% to 11%, the same prevalence as in the normative population; in branch 1 the score dropped from 14% to 13%, and in branch 2 it dropped from 23% to 8%. The prevalence of externalizing problems dropped too, from 12% to 8%: in branch 1 it was unchanged at 10%, and in branch 2 it dropped from 14% to 7%. The decrease in prevalence of internalizing problems after treatment, from 16% to 14%, was not significant. CONCLUSION: More behavioral problems were found in dysfunctional voiding than in urge syndrome, but none of the abnormal scores related to the outcome of European Bladder Dysfunction Study treatment for incontinence. With such treatment, both the total behavior problem score and the score for externalizing problems returned to normal, but the score for internalizing problems did not change. The drops in prevalence are statistically significant only in dysfunctional voiding.

Circadian variation of voided volume in normal school-age children.

Functional bladder capacity (FBC) and urine output are important variables in the management of incontinence and nocturnal enuresis. The lack of reference ranges for FBC vs. age, and the arbitrarily defined time-windows for measuring urine output, impede the clinical use of these variables in children. To solve these impediments, we had 26 girls and 28 boys, between 6 and 12 years of age, collect, measure, time, and sample every voiding, using 72-h frequency-volume charts; all samples were analysed for osmolality and creatinine concentration. Voided volumes show a very wide range (10-550 ml) and a subset that is significantly larger than all other voidings: early morning voidings (EMV). The individual maximum voided volume (MVV) belongs to the category of EMV in 74% of the children. MVV, the measure for FBC, fits the 5-95% centiles that have been published for cystographic bladder capacity for age in normal children; all other voiding are mostly below the 5% centile. Voided volume plotted vs. corresponding urine output rate shows that, with output rates below 50 ml/h, rest-phase bladder filling always results in significantly larger voidings (EMV) than activity-phase bladder filling. Two circadian rhythms seem to be involved, one for urine output, and another for inhibition of bladder contractility. With hourly population averages of individual urine and osmole output rates plotted on a time scale, circadian patterns appear; these patterns are masked when urine output is collected in blocks of 6, 8, or 12 h. Both plots are promising tools for studying the pathophysiology of voided volume vs. urine output, e.g. in children with nocturnal enuresis.

Self-reported urinary incontinence, voiding frequency, voided volume and pad-test results: variables in a prospective study in children.

OBJECTIVE: To determine the congruence between self-reported and objective data on incontinence, voided volume (VV) and voiding frequency (VF), in a prospective study of treatment of functional urinary incontinence (UI) due to urge syndrome or dysfunctional voiding in children. PATIENTS AND METHODS: In all, 202 children, enrolled in the European Bladder Dysfunction Study (EBDS), provided self-reported data on UI, VV and VF, before and after treatment, with validated questionnaires and 72-h voiding diaries. Objective data were obtained with uroflowmetry and a 12-h pad test, also before and after treatment. Questionnaires and diaries were checked and scored by a urotherapist, at scheduled office visits that were combined with uroflowmetry. RESULTS: At entry, parents under-reported UI on the questionnaires in 45% of cases, compared with the urotherapist's scores, and the 12-h pad test sensitivity for UI was only 64% (95% confidence interval 55-73%). The voiding diaries had inconsistent entries on UI and on VV. VF was overestimated in the questionnaires and underestimated in the diaries, compared with the urotherapist's scores. A VF of >7/day decreased significantly after EBDS treatment, but with no correlation with treatment outcome. The mean VV increased significantly after treatment for UI, also with no correlation with treatment outcome. CONCLUSIONS: Voiding diaries and questionnaires are useful tools for charting individual treatment and for screening, but they are ill-suited to documenting outcome variables in urge syndrome or dysfunctional voiding, because of over- and under-reporting. VV and VF lack specificity as outcome variables in children with urge syndrome or dysfunctional voiding. The 12-h pad test is not sensitive enough to complement self-reported symptoms of UI in children with urge syndrome or dysfunctional voiding. Clinical studies on UI rely on complaints and self-reported symptoms, but in children the reporting should be supervised by a trained urotherapist, to provide the necessary checks and balances.

Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.

PURPOSE: We assessed prospectively the efficacy of holding exercises and/or antimuscarinics (oxybutynin chloride and placebo) for increasing maximum voided volume in prepubertal children with monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: We randomly allocated 149 children to 5 groups, namely holding exercises with placebo (group A), holding exercises with oxybutynin (group B), placebo alone (group C), oxybutynin alone (group D) and alarm treatment (controls, group E). Maximum voided volume was the greatest voided volume from a 48-hour bladder diary, and holding exercise volume was the greatest volume produced with postponement of voiding after a fluid load, once daily for 4 days. Study medication, holding exercise procedures and alarm treatment were administered for 12 weeks. RESULTS: Holding exercises combined with placebo or oxybutynin significantly increased holding exercise volume and maximum voided volume, by 25% (p <0.001) and 21% (p <0.01), respectively, in group A, and by 43% (p <0.001) and 41% (p <0.001), respectively, in group B. Medication without holding exercises (groups C and D) did not increase holding exercise volume or maximum voided volume, and in these groups oxybutynin was not significantly superior to placebo. A borderline increase in holding exercise volume did not affect maximum voided volume in group E. Monosymptomatic nocturnal enuresis response was significantly lower with all 4 holding exercise volume modulating treatments (7%) compared to alarm therapy (73%). CONCLUSIONS: In the treatment of children with monosymptomatic nocturnal enuresis maximum voided volume can be increased significantly through holding exercises, but not with oxybutynin chloride alone. Compared to controls, increasing maximum voided volume had a minimal effect on monosymptomatic nocturnal enuresis.

Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial.

PURPOSE: To investigate the role of prophylactic cranial irradiation (PCI) within a trimodality protocol (chemotherapy, chemoradiotherapy, surgery) for patients with operable stage IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: After mediastinoscopic staging, patients with operable stage IIIA NSCLC were enrolled to a German multicenter trial and randomly assigned to receive either primary resection followed by adjuvant thoracic radiation therapy (50 to 60 Gy; arm A) or preoperative chemotherapy (cisplatin/etoposide [PE]; three cycles) followed by concurrent chemoradiotherapy (PE plus 45 Gy; 1.5 Gy twice per day) and definitive surgery (arm B), respectively. Patients in arm B were scheduled to receive PCI (30 Gy; 2 Gy daily fractions). RESULTS: One hundred twelve patients were randomly assigned between November 1994 and July 2001. One hundred six patients were eligible (arm A: 51, arm B: 55), 90 males and 16 females, 50 with squamous cell, 16 with large cell, five with adenosquamous, and 35 with adenocarcenoma (median age, 57 years; range, 37 to 71 years). Forty-three patients received PCI as scheduled in arm B. Eleven long-term survivors (arm A: four; arm B: seven) underwent a comprehensive neuropsychological examination. PCI significantly reduced the probability of brain metastases as first site of failure (7.8% at 5 years v 34.7%; P = .02), the overall brain relapse rate was reduced comparably (9.1% at 5 years v 27.2%; P = .04). A slightly reduced neurocognitive performance in comparison with the age-matched normal population was found for patients in both treatment groups. No significant difference between patients who were treated with or without PCI could be noted. CONCLUSION: PCI is effective in preventing brain metastases following this aggressive trimodality approach. Neurocognitive late effects are not significantly different between patients treated with or without PCI.

Reference ranges for cystographic bladder capacity in children-with special attention to vesicoureteral reflux.

PURPOSE: Linear correlations for cystometric/cystographic bladder capacity with age universally serve as clinical yardsticks in pediatric urology and nephrology. However, these correlations do not account for growth or the range in values, as the relation of cystometric/cystographic bladder capacity with age is nonlinear. Also, vesicoureteral reflux might influence the size of cystometric/cystographic bladder capacity, since small and large bladder capacities have been reported in conjunction with reflux. We decided to use the data sets of the International Reflux Study in Children to construct full reference ranges for cystometric/cystographic bladder capacity and age, for comparison with existing reference ranges in normal children, and to study the relation between bladder capacity and refluxing volume. MATERIALS AND METHODS: In the International Reflux Study in Children 386 patients with grade III or IV vesicoureteral reflux were followed with isotope cystography for 10 years. To follow the grade of reflux, x-ray cystography was also used at 60-month intervals. The 386 children, who were 1 month to 12 years old, were randomized into 2 groups-those undergoing surgery and those receiving medical treatment. For both groups data were available on cystometric/cystographic bladder capacity, refluxing volume, reflux grade and reflux outcome. RESULTS: The distribution of cystometric/cystographic bladder capacity vs age is logarithmic, with a wide range between the 5th and 95th percentiles, and a clear nonlinear relation between bladder capacity and age (p < 0.001). Gender has no influence on cystometric/cystographic bladder capacity. No difference in bladder capacity exists between persistence or resolution of vesicoureteral reflux (p < 0.78), between grade III and grade IV reflux (p < 0.94), or between unilateral and bilateral reflux (p < 0.74). Thus, refluxing volume correlated only with reflux grade, not with cystometric/cystographic bladder capacity or age. CONCLUSIONS: With or without vesicoureteral reflux values for cystometric/cystographic bladder capacity range widely in children, and correlate logarithmically with age. For clinical decisions the full reference range for age, flanked by the 5th and 95th percentiles, should be used to assess individual values for cystometric/cystographic bladder capacity, rather than linear functions.