Voiding camp: A successful and unique bladder rehabilitation program for children with urinary incontinence.

INTRODUCTION & BACKGROUND: Standard urotherapy is a well-established treatment for children with incontinence, although it is often challenging for both child and parents, and not always successful. As an alternative, several in- and outpatient bladder training programs have shown positive results on achieving continence. However, the disadvantage is the hospital environment, which can be more stressful for the child, and also quite expensive for society. OBJECTIVE: The aim was to evaluate the outcome on achieving continence following a voiding camp, where standard urotherapy was applied during a one-week stay at a regular summer youth camp, outside the hospital. STUDY DESIGN: Retrospective analysis of 105 children with urinary incontinence, followed in an expert centre for urinary incontinence for at least one year. Data at 7 different time points, before, during and until 6 months after voiding camp were collected. RESULTS: Even though all children had regular follow-up in an expert centre for urinary incontinence for at least one year before participating voiding camp, only 15% of the children reached the recommended amount of daily fluid intake (1.5 L/day). Once minimal daily fluid intake was re-established during the voiding camp, an immediate increase in the maximum voided volume (MVV), and a decrease in the number of wet days and wet nights per week was noted. This effect on a higher MVV remained even 3 months after voiding camp. DISCUSSION: Although sufficient daily fluid intake is a well-established part of standard urotherapy, up until now there was no data that proved the positive impact of sufficient daily fluid intake on bladder volume training and achieving continence in children. CONCLUSION: Voiding camp, as an unique bladder rehabilitation program for children with incontinence, is a successful alternative treatment option. Optimizing the daily fluid intake during voiding camp had a major positive impact on bladder volume training and achieving continence in children.

The development of the Belgian paediatric clinical trial network.

Paediatric clinical trials are critical to ensure that medications prescribed to children are safe and effective. However, evidence-based dosing and labelling of such medications remain limited, and most clinical trials in paediatrics fail. Factors for lack of trial completion include performance at site level (limited patient recruitment, limited site staff experience and lack of infrastructure), the sponsor team (limited paediatric specific expertise in design, uncertainties on robustness of biomarkers or outcome variables) as well as regulatory and administrative burdens. As a result of the growing demand for site support, the Belgian Paediatric Clinical Research Network (BPCRN) established in 2009 has been relaunched in 2018 to improve paediatric clinical trials, with the support of innovative-medicines-initiative 2 (IMI2) pan-European network conect4children (c4c) and the transatlantic network I-ACT for Children (US).This paper highlights the formation of the BPCRN and the practical insights it offers for advancing paediatric clinical trials through national networks. A national network can improve trial quality, safety and efficiency, provide clinical research expertise, identify suitable sites, and help with troubleshooting of common trial issues. The BPCRN's centralized approach has advanced paediatric clinical trials by streamlining communication and standardizing trial conduct. Challenges and opportunities have arisen, including a relaunch in 2018, orphan medicine trials, and network sustainability. Collaboration between network activities, government support, site-level improvements, efficient communication, and interaction with industry are key to achieve lasting transformation in paediatric medicine research.

The long-term added value of voiding school for children with refractory non-neurogenic overactive bladder: an inpatient bladder rehabilitation program.

INTRODUCTION & BACKGROUND: Despite adequate management, 20% of children with overactive bladder (OAB) syndrome fail to improve their bladder function. To approach the need for alternative strategies, an inpatient bladder rehabilitation 'voiding school' program was established. OBJECTIVE: The objective of this study was to evaluate the short- and long-term (1-year follow-up) outcome of this voiding school program in children with refractory OAB. In addition, the authors aimed to identify which children achieved the best outcomes with this voiding school program. STUDY DESIGN: The charts of all children (n = 357, mean age: 9.7 ± 2.0 years, 63.6% boys) with refractory OAB who attended voiding school between 2000 and 2010 were reviewed. A linear mixed model with random intercept was used to evaluate the incontinence (expressed by enuresis and daytime incontinence voiding scores) and maximal voiding volume (MVV). RESULTS & DISCUSSION: This study demonstrated an overall beneficial long-term effect of the inpatient program on day- and night-time incontinence, in which 36.6% of children achieved dryness during day- and night-time. In addition, the mean overall decline in the number of wet nights and days declined with 4 extra dry days and/or nights per week, in comparison with the level of continence before attending the voiding school program. In contrast, only a temporary increase in MVV was seen, however, without relapse incontinence. At last, the authors identified the negative impact of decreasing age, male sex, dysfunctional voiding and nocturnal polyuria on the overall outcome of the inpatient program. CONCLUSION: An inpatient rehabilitation 'voiding school' program is a successful and safe treatment modality for children with refractory OAB that results in long-term significant increase of continence, as well as amelioration in degree of severity. The worst outcomes of this voiding school program were detected in children with young age, who were boys, or had associated nocturnal polyuria, dysfunctional voiding, and/or faecal incontinence.

CYP3A4 is a crosslink between vitamin D and calcineurin inhibitors in solid organ transplant recipients: implications for bone health.

The use of calcineurin inhibitors (CNIs) and vitamin D deficiency may contribute to the pathogenesis of post-transplant bone disease. CNIs and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are substrates of the drug-metabolizing enzyme CYP3A4. This review summarizes the indications for the use of activated vitamin D analogs in post-transplant care and the current knowledge on the impact of CNIs on bone. We searched for clinical evidence of the interaction between CNIs and 1,25(OH)2D3. We also provide an overview of the literature on the interplay between vitamin D metabolism and CYP3A4 in experimental and clinical settings and discuss its possible implications for solid organ transplant recipients. In conclusion, there is a body of evidence on the interplay between vitamin D and the drug-metabolizing enzyme CYP3A4, which may have therapeutic implications.

Circadian Rhythm of Glomerular Filtration and Solute Handling Related to Nocturnal Enuresis.

PURPOSE: Although nocturnal polyuria in patients with monosymptomatic enuresis can largely be explained by the decreased nocturnal vasopressin secretion hypothesis, other circadian rhythms in the kidney also seem to have a role. We recently documented an absent day/night rhythm in a subgroup of desmopressin refractory cases. We explore the importance of abnormal circadian rhythm of glomerular filtration and tubular (sodium, potassium) parameters in patients with monosymptomatic enuresis. MATERIALS AND METHODS: In this retrospective study of a tertiary enuresis population we collected data subsequent to a standardized screening (International Children's Continence Society questionnaire), 14-day diary for nocturnal enuresis and diuresis, and 24-hour concentration profile. The study population consisted of 139 children with nocturnal enuresis who were 5 years or older. Children with nonmonosymptomatic nocturnal enuresis were used as controls. RESULTS: There was a maintained circadian rhythm of glomerular filtration, sodium, osmotic excretion and diuresis rate in children with monosymptomatic and nonmonosymptomatic nocturnal enuresis, and there was no difference between the 2 groups. Secondary analysis revealed that in patients with nocturnal polyuria (with monosymptomatic or nonmonosymptomatic nocturnal enuresis) circadian rhythm of glomerular filtration, sodium and osmotic excretion, and diuresis rate was diminished in contrast to those without nocturnal polyuria (p <0.001). CONCLUSIONS: Circadian rhythm of the kidney does not differ between patients with nonmonosymptomatic and monosymptomatic enuresis. However, the subgroup with enuresis and nocturnal polyuria has a diminished circadian rhythm of nocturnal diuresis, sodium excretion and glomerular filtration in contrast to children without nocturnal polyuria. This observation cannot be explained by the vasopressin theory alone.

Neuropsychological functioning related to specific characteristics of nocturnal enuresis.

INTRODUCTION/BACKGROUND: There is a high comorbidity demonstrated in the literature between nocturnal enuresis and several neuropsychological dysfunctions, with special emphasis on attention deficit hyperactivity disorder (ADHD). However, the majority of the psychological studies did not include full non-invasive screening and failed to differentiate between monosymptomatic nocturnal enuresis (MNE) and non-MNE patients. OBJECTIVE: The present study primarily aimed to investigate the association between nocturnal enuresis and (neuro)psychological functioning in a selective homogeneous patient group, namely: children with MNE and associated nocturnal polyuria (NP). Secondly, the study investigated the association between specific characteristics of nocturnal enuresis (maximum voided volume, number of wet nights and number of nights with NP) and ADHD-inattentive symptoms, executive functioning and quality of life. STUDY DESIGN: The psychological measurements were multi-informant (parents, children and teachers) and multi-method (questionnaires, clinical interviews and neuropsychological testing). RESULTS: Thirty children aged 6-16 years (mean 10.43 years, SD 3.08) were included. Of them, 80% had at least one psychological, motor or neurological difficulty. The comorbid diagnosis of ADHD, especially the predominantly inattentive presentation, was most common. According to the teachers, a low maximum voided volume (corrected for age) was associated with more attention problems, and a high number of nights with NP was associated with more behaviour-regulation problems. No significant correlations were found between specific characteristics of enuresis and quality of life. Details are demonstrated in Table. DISCUSSION: The children were recruited from a tertiary referral centre, which resulted in selection bias. Moreover, NP was defined as a urine output exceeding 100% of the expected bladder capacity for age (EBC), and not according to the expert-opinion-based International Children's Continence Society norm of 130% of EBC. The definition for NP of a urine output exceeding 100% of the EBC is more in line with the recent findings of the Aarhus group. CONCLUSIONS: For children with MNE and associated NP, a high comorbidity with the predominantly inattentive presentation of ADHD was demonstrated. Children experienced problems with daytime functioning in relation to their wetting problem at night. According to the teachers, a low maximum voided volume was associated with more attention problems, and a high number of nights with NP was associated with more behaviour-regulation problems. Although comorbidity is still the appropriate word to use, the observation favours a more complex pathogenesis of enuresis with a common pathway in the central nervous system, including: neurotransmitters, influencing neuropsychological functioning as well as sleep, circadian rhythm of diuresis and bladder function control.

Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study.

BACKGROUND: Bi-allelic CYP24A1 mutations can cause idiopathic infantile hypercalcemia (IIH), adult-onset nephrocalcinosis, and possibly bone metabolism disturbances. It is currently unclear if heterozygous carriers experience clinical problems or biochemical abnormalities. Our objective is to gain insight in the biochemical profile and health problems in CYP24A1 heterozygotes. STUDY DESIGN: Cross-sectional evaluation of participants. Data of previously reported carriers are reviewed. SETTING AND PARTICIPANTS: Outpatient clinic of a tertiary care hospital. Participants were eight family members of an infant with a well-characterized homozygous CYP24A1 mutation c.1186C>T p.(Arg396Trp). OUTCOMES: Serum vitamin D metabolites. Symptoms or biochemical signs of hypercalcemia, hypercalciuria or nephrocalcinosis. Bone health in heterozygous as compared to wild type (WT) subjects. MEASUREMENTS: Genotyping by Sanger sequencing; vitamin D metabolites by liquid chromatography tandem mass spectrometry; renal, calcium and bone markers by biochemical analyses; presence of nephrocalcinosis by renal ultrasound; bone health by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: Six participants were heterozygous carriers of the mutation. None of the heterozygous subjects had experienced IIH. One had a documented history of nephrolithiasis, two others had complaints compatible with this diagnosis. No major differences between WT and heterozygous subjects were found regarding bone health, serum or urinary calcium or 25OHD/24,25(OH)2D ratio. Literature reports on three out of 33 heterozygous cases suffering from IIH. In all three, the 25OHD/24,25(OH)2D ratio was highly elevated. Nephrocalcinosis was frequently reported in family members of IIH cases. LIMITATIONS: Small sample size, lack of a large control group. CONCLUSIONS: Our and literature data suggest that most heterozygous CYP24A1 mutation carriers have a normal 25OHD/24,25(OH)2D ratio, are usually asymptomatic and have a normal skeletal status but may possibly be at increased risk of nephrocalcinosis. A review of the available literature suggests that an elevated 25OHD/24,25(OH)2D ratio may be associated with symptoms of IHH, irrespective of carrier status.

Propylthiouracil induced ANCA-associated vasculitis in a 14-year-old girl.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) are the serologic hallmark of ANCA-associated primary small-vessel vasculitides (AAVs), but these antibodies have also been described in other autoimmune diseases such as inflammatory bowel diseases. Furthermore, different drugs are linked to the induction of ANCA, including propylthiouracil (PTU). However progression into clinical overt vasculitis is less common. CASE-DIAGNOSIS/TREATMENT: We describe the case of a young girl with Graves' disease presenting with fatigue, fever, episcleritis and arthritis. The unexpected double myeloperoxidase/proteinase 3-ANCA positivity triggered a multidisciplinary diagnostic work-up and resulted in the diagnosis of a clinically overt PTU-induced AAV. After PTU-withdrawal and treatment with high-dose corticosteroids, a favorable clinical and biochemical evolution was obtained. CONCLUSIONS: The use of PTU in the management of hyperthyroidism is not considered first-line treatment in Europe and is even less commonly used in children. Nevertheless, pediatricians should be aware of the possibility of PTU-induced AAV, especially in the presence of multiple ANCA reactivities. Therefore, the use of this drug should be weighed carefully in children.

Sleep fragmentation and increased periodic limb movements are more common in children with nocturnal enuresis.

AIM: To determine sleep fragmentation in children with nocturnal enuresis (NE). METHODS: Paediatricians assessed NE parameters in children referred to an enuresis clinic. Control subjects, matched by age and gender and without incontinence or (un)treated NE, were recruited from the paediatric sleep clinic regardless of their sleep problem. Sleep was investigated by one overnight video-polysomnography in both groups. RESULTS: The study group comprised 67 children with proven NE (50 boys and 17 girls between six and 16 years: 11.1 ± 2.8 SD). They were matched with 67 control subjects (47 boys and 20 girls aged between six and 16 years: 11.0 ± 2.9 SD). Children with NE had a higher incidence of periodic limb movements associated with cortical arousals in their sleep. They displayed significant higher periodic limb movement index, arousal index and awakening index than the control group. CONCLUSION: Children with NE displayed higher sleep fragmentation and periodic limb movements in sleep than the control children with a possible sleep disorder without NE. The findings emphasise the central involvement of the pathophysiology of NE and the multifactorial nature of the condition.

Disparities in policies, practices and rates of pediatric kidney transplantation in Europe.

We aimed to provide an overview of kidney allocation policies related to children and pediatric kidney transplantation (KTx) practices and rates in Europe, and to study factors associated with KTx rates. A survey was distributed among renal registry representatives in 38 European countries. Additional data were obtained from the ESPN/ERA-EDTA and ERA-EDTA registries. Thirty-two countries (84%) responded. The median incidence rate of pediatric KTx was 5.7 (range 0-13.5) per million children (pmc). A median proportion of 17% (interquartile range 2-29) of KTx was performed preemptively, while the median proportion of living donor KTx was 43% (interquartile range 10-52). The median percentage of children on renal replacement therapy (RRT) with a functioning graft was 62%. The level of pediatric prioritization was associated with a decreased waiting time for deceased donor KTx, an increased pediatric KTx rate, and a lower proportion of living donor KTx. The rates of pediatric KTx, distribution of donor source and time on waiting list vary considerably between European countries. The lack of harmonization in kidney allocation to children raises medical and ethical issues. Harmonization of pediatric allocation policies should be prioritized.

Oral lyophylizate formulation of desmopressin: superior pharmacodynamics compared to tablet due to low food interaction.

PURPOSE: Desmopressin is a standard treatment for monosymptomatic nocturnal enuresis. Different formulations are promoted as bioequivalent, although these claims are not supported by comparative pharmacodynamic data in children. Food interaction is known to influence the bioavailability of desmopressin. We compared the pharmacodynamics of the 2 most frequently used desmopressin formulations, tablet and lyophilizate, with a standardized meal, allowing extrapolation to clinical reality, where the interval between evening meal and medication intake is limited for school-age children. We hypothesized there would be a faster pharmacodynamic response, and greater concentrating and antidiuretic activity for the fast dissolving (melt) formulation compared to the tablet with simultaneous food intake. MATERIALS AND METHODS: Two tests were performed on separate days in identical standardized conditions, starting with a 15 ml/kg water load. After achieving maximal diluting capacity a standardized meal was administered, followed by desmopressin tablet (t test) or melt (M-test). Diuresis rate and urinary osmolality were measured hourly. Paired data from 4 girls and 15 boys with a mean age of 12.1 years were obtained. RESULTS: In the early response phase more than 25% of patients had a higher diuresis rate with tablet vs melt formulation, reaching statistical significance in the plateau phase (urine collected at hours 3 to 5, p <0.02) and in duration of action (urine collected at hours 5 to 8, p <0.005). For desmopressin melt smaller standard deviations in diuresis rate were remarkable. Concentrating capacity demonstrated no significant differences between formulations in the early response phase, in contrast to the plateau phase (p <0.036) and duration of action (p <0.001). CONCLUSIONS: With meal combination desmopressin melt formulation has a superior pharmacodynamic profile to tablet, making it more suitable for the younger age group with a limited interval between meal and drug administration.

Hypercalciuria is related to osmolar excretion in children with nocturnal enuresis.

PURPOSE: We evaluated the incidence of hypercalciuria, defined as urinary calcium-to-creatinine ratio greater than 0.21 mg/mg, in children with nocturnal enuresis, and the association with concurrent values of diuresis and osmolar excretion. MATERIALS AND METHODS: A total of 550 children admitted to a tertiary university center were included in the study. A 24-hour urine collection was performed in 8 sampling periods for measurement of calcium excretion, osmolality and diuresis. RESULTS: Of the children with nocturnal enuresis 12% had 24-hour hypercalciuria. Up to 29% of the timed urine samples exhibited hypercalciuria. There was a significant correlation between calcium excretion and nocturnal diuresis volume (polyuria), low urinary osmolality, and increased sodium and osmolar excretion of nighttime urine samples (all p <0.001). CONCLUSIONS: Patients referred to a tertiary enuresis center have a high incidence of hypercalciuria. However, the significant correlation between hypercalciuria and osmolar excretion and diuresis suggests that it is a comorbid factor rather than a primary pathogenic factor. As such, we cannot confirm the data from Italian studies relating nocturnal enuresis to primary hypercalciuria, and suggest instead an association with nutritional intake.

Desmopressin resistant nocturnal polyuria may benefit from furosemide therapy administered in the morning.

PURPOSE: There is increasing evidence that a subgroup of patients with monosymptomatic nocturnal enuresis and nocturnal polyuria resistant to desmopressin may have an abnormal circadian rhythm of renal tubular sodium handling. The pathogenesis of this phenomenon remains to be elucidated. If the increased sodium excretion overnight results in desmopressin resistance, decreasing the sodium excretion overnight may result in subsequently better desmopressin response. MATERIALS AND METHODS: We conducted a pilot study of the anti-enuretic and antidiuretic effects of desmopressin combined with 0.5 mg/kg furosemide daily in patients with desmopressin resistant nocturnal polyuria despite dietary sodium and protein restriction. Values were plotted against the reference frame of a desmopressin responsive enuresis group. RESULTS: Baseline values revealed significantly lower urinary osmolality and higher diuresis rate overnight compared to the reference population (monosymptomatic nocturnal enuresis desmopressin responders). Introduction of desmopressin resulted in normalization of nocturnal urinary osmolality. However, nocturnal polyuria persisted, despite reaching maximal urinary concentration overnight. Although protein and sodium restriction resulted in a significant decrease in urinary osmolality and diuresis rate, the difference was not clinically important enough to reach normal values or to achieve continence. Furosemide in the morning resulted in a significant increase in diuresis and osmotic and sodium excretion during the day, and decreased nighttime diuresis and osmotic excretion. In 9 of 12 patients the nocturnal antidiuretic effect resulted in an anti-enuretic effect, defined as enuresis less than 1 wet night per month. In 3 patients insufficient anti-enuretic effects were obtained despite significant antidiuresis. CONCLUSIONS: This pilot study clearly demonstrates that introduction of early morning furosemide results in a significantly lower nocturnal diuresis rate. Reduced diuresis associated with unchanged urinary osmolality results in decreased nocturnal osmotic excretion in compensation for increased osmotic (sodium) excretion during the daytime.

Nocturnal polyuria is related to 24-hour diuresis and osmotic excretion in an enuresis population referred to a tertiary center.

PURPOSE: Primary nocturnal enuresis is a heterogeneous disorder, causing a mismatch between overnight diuresis volume and functional bladder capacity. Despite increasing insights in pathogenesis, lack of efficacy of the available treatments is a major problem. We evaluated characteristics of bladder volume and diuresis rate in patients with nocturnal enuresis referred to a tertiary enuresis center. MATERIALS AND METHODS: Noninvasive screening including maximal voided volume, 24-hour circadian rhythm of diuresis and osmotic excretion from 1,000 consecutive patients. RESULTS: Of the patients referred as having monosymptomatic nocturnal enuresis 32% were subsequently classified as having nonmonosymptomatic nocturnal enuresis. Differences in bladder volume and nocturnal diuresis characteristics between the monosymptomatic nocturnal enuresis and nonmonosymptomatic nocturnal enuresis groups were minimal. CONCLUSIONS: The most common observation is a nocturnal diuresis volume greater than maximal voided volume, which in both groups can be caused by nocturnal polyuria or small bladder volume for patient age. The most striking observation is that the positive correlation between nocturnal diuresis volume rate and nocturnal osmotic excretion and 24-hour fluid intake is significantly higher than with the inversed urinary osmolality overnight, which is not only unexpected based on the theory of the primary suppression of vasopressin levels overnight, but also points to a more important role for nutritional and fluid intake than accepted, if not in the primary pathogenesis, then at least in therapy resistance.

Nocturnal polyuria is related to absent circadian rhythm of glomerular filtration rate.

PURPOSE: Monosymptomatic nocturnal enuresis is frequently associated with nocturnal polyuria and low urinary osmolality during the night. Initial studies found decreased vasopressin levels associated with low urinary osmolality overnight. Together with the documented desmopressin response, this was suggestive of a primary role for vasopressin in the pathogenesis of enuresis in the absence of bladder dysfunction. Recent studies no longer confirm this primary role of vasopressin. Other pathogenetic factors such as disordered renal sodium handling, hypercalciuria, increased prostaglandins and/or osmotic excretion might have a role. So far, little attention has been given to abnormalities in the circadian rhythm of glomerular filtration rate. We evaluated the circadian rhythm of glomerular filtration rate and diuresis in children with desmopressin resistant monosymptomatic nocturnal enuresis and nocturnal polyuria. MATERIALS AND METHODS: We evaluated 15 children (9 boys) 9 to 14 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria resistant to desmopressin treatment. The control group consisted of 25 children (12 boys) 9 to 16 years old with monosymptomatic nocturnal enuresis without nocturnal polyuria. RESULTS: Compared to the control population, children with nocturnal polyuria lost their circadian rhythm not only for diuresis and sodium excretion but also for glomerular filtration rate. CONCLUSIONS: Patients with monosymptomatic nocturnal enuresis and nocturnal polyuria lack a normal circadian rhythm for diuresis and sodium excretion, and the circadian rhythm of glomerular filtration rate is absent. This absence of circadian rhythm of glomerular filtration rate and/or sodium handling cannot be explained by a primary role of vasopressin, but rather by a disorder in circadian rhythm of renal glomerular and/or tubular functions.

Partial response to intranasal desmopressin in children with monosymptomatic nocturnal enuresis is related to persistent nocturnal polyuria on wet nights.

PURPOSE: The anti-incontinence effect of desmopressin resides in its concentrating capacity and antidiuretic properties. We compared nighttime urine production on wet and dry nights in a highly selected study population of children with monosymptomatic nocturnal enuresis associated with proved nocturnal polyuria who responded only partially to intranasal desmopressin. MATERIALS AND METHODS: We retrospectively analyzed 39 home recordings of nocturnal urine production and maximum voided volume in children 7 to 19 years old (median 8.9) with monosymptomatic nocturnal enuresis with nocturnal polyuria who had a partial response to desmopressin. Nocturnal diuresis volume and maximum voided volume were documented at baseline (14 days) and during 3 months of followup. RESULTS: Baseline nocturnal urine output (439 +/- 39 ml) was significantly higher than the maximum voided volume (346 +/- 93 ml, p <0.01). During desmopressin treatment nocturnal urine output on wet nights (405 +/- 113 ml) differed significantly from that on dry nights (241 +/- 45 ml). During treatment nocturnal urine output on wet nights did not differ from baseline values. CONCLUSIONS: Persistence of nocturnal polyuria on wet nights in partial desmopressin responders may be related to an insufficient antidiuretic effect. In addition to poor compliance and suboptimal dosing, the poor bioavailability of intranasal desmopressin may be a pathogenic factor. Further prospective studies are needed.

The aromatic cluster in KCHIP1b affects Kv4 inactivation gating.

The KChIP1b splice variant has been shown to induce slow recovery from inactivation for Kv4.2 whereas KChIP1a enhanced the recovery. Both splice variants differ only by the insertion of the exon1b, rich in aromatic residues (5/11). We analysed in detail the modifications of Kv4.2 gating induced by the KChIP1b splice variant and the role for the aromatic cluster in KChIP1b in inducing these changes. By substituting alanine for the aromatic residues individually or in combination, we could convert the KChIP1b recovery behaviour into that of KChIP1a. The replacement of one or two aromatic residues resulted in a partial restitution of the KChIP1a recovery behaviour. When three aromatic residues were replaced in the exon1b, the recovery from inactivation was fast with time constants that were similar to those obtained with KChIP1a. Moreover, similar findings were observed for closed state inactivation and for the voltage dependence of inactivation. Thus, reduction of the side chain bulkiness in exon1b resulted in the conversion of the KChIP1b phenotype into the KChIP1a phenotype. These results indicate that the aromatic cluster in exon1b modulates the transitions towards and from the closed inactivated states and the steady state distribution over the respective states.

A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes.

The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c.1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser.

Renal functional changes in relation to hemodynamic parameters during exercise test in normoalbuminuric insulin-dependent children.

AIM: To examine the relationship between filtration fraction and systemic vasculopathy, in normoalbuminuric insulin-dependent diabetic adolescents. METHODS: We calculated filtration fraction from measured glomerular filtration rate and renal plasma flow during a hypotonic saline perfusion test in 30 normotensive adolescent diabetic patients (9-19 years), with a mean duration of diabetes of 7.4 years. Blood pressure and heart rate were measured in basal conditions, during a 24-h ambulatory monitoring and during a dynamic exercise test on a cycle ergometer and peripheral vascular resistance was calculated. RESULTS: Filtration fraction was increased in the diabetic children compared with controls (30+/-6% vs. 22+/-4%, p<0.001), while renal plasma flow was significantly lower (453+/-133 mL/min/1.73 m2 vs. 593+/-155 mL/min/1.73 m2, p<0.001). Peripheral vascular resistance was significantly higher at peak exercise in diabetic children compared to controls (16.3+/-1.3 mmHg/L min m2 vs. 11.4+/-0.5 mmHg/L min m2, p<0.01). CONCLUSION: These results indicate that in young patients with IDDM, without apparent nephropathy or apparent systemic vasculopathy, filtration fraction is increased, suggesting an increased intraglomerular pressure. The associated reduced decrease of peripheral vascular resistance (increased diastolic blood pressure during exercise) suggests that renal functional abnormalities may be partly explained by a systemic vasculopathy, also present in the kidney.