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The volume, diversity and velocity of biomedical data are exponentially increasing providing petabytes of new neuroimaging and genetics data every year. At the same time, tens-of-thousands of computational algorithms are developed and reported in the literature along with thousands of software tools and services. Users demand intuitive, quick and platform-agnostic access to data, software tools, and infrastructure from millions of hardware devices. This explosion of information, scientific techniques, computational models, and technological advances leads to enormous challenges in data analysis, evidence-based biomedical inference and reproducibility of findings. The Pipeline workflow environment provides a crowd-based distributed solution for consistent management of these heterogeneous resources. The Pipeline allows multiple (local) clients and (remote) servers to connect, exchange protocols, control the execution, monitor the states of different tools or hardware, and share complete protocols as portable XML workflows. In this paper, we demonstrate several advanced computational neuroimaging and genetics case-studies, and end-to-end pipeline solutions. These are implemented as graphical workflow protocols in the context of analyzing imaging (sMRI, fMRI, DTI), phenotypic (demographic, clinical), and genetic (SNP) data.

Many contemporary neuroscientific investigations face significant challenges in terms of data management, computational processing, data mining, and results interpretation. These four pillars define the core infrastructure necessary to plan, organize, orchestrate, validate, and disseminate novel scientific methods, computational resources, and translational healthcare findings. Data management includes protocols for data acquisition, archival, query, transfer, retrieval, and aggregation. Computational processing involves the necessary software, hardware, and networking infrastructure required to handle large amounts of heterogeneous neuroimaging, genetics, clinical, and phenotypic data and meta-data. Data mining refers to the process of automatically extracting data features, characteristics and associations, which are not readily visible by human exploration of the raw dataset. Result interpretation includes scientific visualization, community validation of findings and reproducible findings. In this manuscript we describe the novel high-throughput neuroimaging-genetics computational infrastructure available at the Institute for Neuroimaging and Informatics (INI) and the Laboratory of Neuro Imaging (LONI) at University of Southern California (USC). INI and LONI include ultra-high-field and standard-field MRI brain scanners along with an imaging-genetics database for storing the complete provenance of the raw and derived data and meta-data. In addition, the institute provides a large number of software tools for image and shape analysis, mathematical modeling, genomic sequence processing, and scientific visualization. A unique feature of this architecture is the Pipeline environment, which integrates the data management, processing, transfer, and visualization. Through its client-server architecture, the Pipeline environment provides a graphical user interface for designing, executing, monitoring validating, and disseminating of complex protocols that utilize diverse suites of software tools and web-services. These pipeline workflows are represented as portable XML objects which transfer the execution instructions and user specifications from the client user machine to remote pipeline servers for distributed computing. Using Alzheimer's and Parkinson's data, we provide several examples of translational applications using this infrastructure1. © 2014 Dinov, Petrosyan, Liu, Eggert, Hobel, Vespa, Woo Moon, Van Horn, Franco and Toga.

BACKGROUND: In treating primary nocturnal enuresis the dosages recommended for an intranasal application of dDAVP are 20, 30 or 40 microgram depending on the response. Dosages that take the patient's weight or age into account are not commonly used until now. PATIENTS AND METHODS: In the present prospective study including 43 children therapeutic success was therefore evaluated on the basis of the dosage that was standardized according to both age and weight of the patients. The patients' weight ranged from 16.5 to 98 kg, their age from 6 to 14.9 years. RESULTS: The dDAVP dosages that were applied ranged from 0.3 and 2.4 microgram/kg and 3.74 and 15.3 microgram x age/kg respectively. Therapeutic efficacy was at 63 %. CONCLUSIONS: The results suggest an ideal weight-related dosage of 1 microgram x weight or rather an age- and weight-related dosage of 8 microgram x weight/age. A higher dosage evidently is of little use since there was a significant difference between the non-responders and the responders (p < 0.01) with the non-responders not even reacting to higher dosages.

Background: Although frequently observed, the etiology of idiopathic hypercalciuria (IHC) remains largely unknown. A common hypothesis postulates intestinal hyperabsorption and/or a primary renal leak as the pathophysiological basis. The aim of our study was to investigate the regulation pattern of calcium homeostasis in patients with IHC by using a prolonged period of calcium restriction. Methods: Twenty-seven patients with IHC were investigated. After a 3-week run-in period (dietary calcium content 700–1,000 mg/24 h), a standard calcium reduced diet (300 mg/24 h) was given for 4 weeks. Thereafter, the participants received again a normal calcium-containing diet. Values for urinary calcium, PTH and calcitriol levels of all participants were obtained at different phases of the study. Forty-three healthy persons served as controls. Results: During calcium restriction, two distinct groups were identified. One group displayed an increase (n = 12) in urinary calcium excretion, the second (n = 15) a marked reduction, respectively. In both groups, the values during calcium restriction were significantly different from baseline (p < 0.01). In the first group, the increase of urinary calcium excretion was accompanied by an increase of PTH and calcitriol. These values were also significantly different from baseline values (p < 0.01). The control group showed decreasing calcium excretion during oral restriction (p < 0.01). Conclusion: Prolonged calcium restriction proved to be useful in distinguishing apparently two major forms of IHC. The fact that one group displayed the same excretion pattern as the control group raises the question if this group just represents the upper limit of a physiological range. These findings may shed new light on diagnosis, pathogenesis and treatment of patients with IHC.

The measurement of urinary enzymes in patients with diabetes mellitus has become a useful additional test for the early detection of nephropathy. Controversy persists concerning methods of measurement since during early stages of insulin-dependent diabetes mellitus children develop the so-called hyperfiltration syndrome. This study was performed to determine whether elevated levels of excreted creatinine influence the determination of the enzyme N-acetyl-beta-D-glucosaminidase (NAG). Reference values for NAG in single-spot urines (units NAG/mmol creatinine) and in 24-h collections (units NAG/l urine) were established in two different groups of 105 and 111 healthy children. NAG was then measured in single-spot urines (as NAG/mmol creatinine) and in collection urines of 30 diabetic children within the same 24-h period and compared with the reference population. These results were compared with hemoglobin (Hb)A1(a-c) and fructosamine values as well as creatinine clearance of the diabetic patients. There was a direct correlation between the NAG levels in single-spot and 24-h urine collections of diabetic patients. However, the NAG/creatinine ratio in the single-spot urines did not correlate with the HbA1(a-c) or fructosamine level. When 24 h collections (expressed as NAG/l) were used, the results correlated well with HbA1(a-c) and fructosamine. There was an inverse correlation between the creatinine clearance and the NAG/creatinine ratio, i.e., a high creatinine clearance correlated with a low NAG/creatinine ratio. This was not the case for 24 h collections (expressed as units/l). Hence, in children with insulin-dependent diabetes mellitus 24-h urine collections should be used for urinanalysis. Parameters should not be related to creatinine, since the ratio of urinary protein and creatinine is unreliable because of the high urinary creatinine during the hyperfiltration state.

The case of a 13.5-year-old girl with acute tubulointerstitial nephritis and uveitis (TINU syndrome) is presented. The etiology of this rare syndrome, which in most cases involves female adolescents and usually regresses spontaneously, is still unknown. An infection-triggered pathological immune reaction has been considered to play a role in the pathogenesis of this disorder. Here we report for the first time the association of TINU syndrome and Epstein-Barr virus infection.

Alarm therapy is a long-established first-line therapy for nocturnal enuresis (NE). Desamino-arginine vasopressin (dDAVP) as alternative first-line therapy was shown to increase the prepulse inhibition (PPI) of startle reflexes, thus supporting the hypothesis of a maturational delay of reflex inhibition in NE. Effects of alarm therapy on PPI have not yet been investigated.The PPI of startle reflexes was measured in 20 children with NE (13 boys, 7 girls, median age 8.5 years, range 5-13) before and after at least 6 weeks of alarm treatment and compared with repeated PPI measurements in 11 healthy controls (7 boys, 4 girls, median age 8 years, range 6-13).In the NE patients, PPI increased from a median baseline of 20-46% under alarm therapy (p = 0.005), with a reduction from a median of 7 to 2 wet nights per week (p = 0.002). The controls showed no difference in PPI (52% median at first, 40% at second measurement, p = 0.966).The increase of PPI trough alarm therapy was comparable with that under dDAVP, suggesting an analogous method of action and explaining the alternative or synergistic effect of both therapies. In addition, it further substantiates the hypothesis of a maturational delay of reflex control in NE.

S’il est vrai que l’edition critique est dans tous les pays une pratique aussi ancienne que celle de la litterature, c’est entre les annees trente et cinquante que l’edition de litterature et de theâtre en langue anglaise est devenue une discipline savante ou « scientifique ». D’abord appliquees aux œuvres de la Renaissance, les nouvelles methodes editoriales influencerent bientot de facon radicale les pratiques d’edition des œuvres litteraires des periodes suivantes. En Amerique du Nord en p...

Purpose: The use of desmopressin in the treatment of primary nocturnal enuresis (PNE) is accepted and based on the fact that this drug leads to renal water reabsorption. However, recent findings have also implicated that desmopressin regulates other molecules, such as sodium and potassium. We investigate if desmopressin influences renal Ca 2 handling. Materials and Methods: A total of 32 children with PNE were enrolled in a prospective study. Patients received a standard 30 g desmopressin intranasally before going to bed. All patients were treated for at least 4 weeks. Desmopressin was then withdrawn and reintroduced after 2 weeks. Urine samples were collected during all 3 phases of the study. Ca 2 measurement was performed in single morning spot urines as well as in 24-hour collections. Additionally, blood was sampled for analysis of Ca 2 . The Wilcoxon signed rank test was used for statistical analysis. Results: Wet nights decreased an average of 4.75 to 1.0 per week with desmopressin treatment. While blood concentrations did not change with or without medication, urinary Ca 2 excretion was significantly higher while patients were treated with desmopressin. This significant result was the same in single spot as well as in 24-hour samples. Conclusions: This study demonstrated the increased excretion of Ca 2 by desmopressin treatment in children with PNE. Since Ca 2 is a crucial molecule in growth and development, this finding indicates the necessity of larger followup studies concerning Ca 2 handling and growth in children on long-term desmopressin treatment.

Purpose: Several studies provide evidence regarding the effect of desmopressin (DDAVP) on the sleep of adults. Therefore, we investigate whether this effect has a role in children with primary nocturnal enuresis treated intranasally with DDAVP. Materials and Methods: A prospective, randomized, placebo controlled, double-blind, crossover study was performed. Patients were assigned to 2 groups by lottery. Arousability was determined by a special bell apparatus with an adjustable sound pressure level. The wet nights per week and the results of the arousal tests were compared using the signed rank test. Results: A total of 20 children with primary nocturnal enuresis 6 to 15 years old were enrolled in the study, 2 of whom had to be excluded. There were no marked differences in age or weight between the groups. The number of wet nights per week decreased significantly with DDAVP treatment. Moreover 14 patients slept more soundly with DDAVP and only 4 were more difficult to awake after the medication. This difference was significant. Conclusions: This study revealed an effect of DDAVP on arousability of enuretic children as well as its previously known action for the treatment of primary nocturnal enuresis. This result is consistent with the known action of DDAVP on sleep of elderly adults. It suggests that the cause of primary nocturnal enuresis lies in the structure of sleep of the affected patients. An accepted therapy of primary nocturnal enuresis (PNE) is treatment with desmopressin (DDAVP).1 This treatment is based on the hypothesis that affected children have insufficient secretion of antidiuretic hormone at night2 and, in combination with a relatively low bladder capacity, nocturnal enuresis occurs.3 However, this concept has been contradicted. 4–6 An emerging hypothesis supported by increasing data indicates that not only renal, but also a central effect of DDAVP may be, at least partially, responsible for the therapeutic effectiveness of DDAVP on children with PNE.7 In the current literature studies provide evidence regarding the effect of DDAVP on sleep of adults.8, 9 Therefore it seems possible that DDAVP also affects the sleep of children treated for PNE. We determined if DDAVP has an influence on the arousability of children with primary nocturnal enuresis. METHODS A prospective, randomized, placebo controlled, doubleblind, crossover trial was conducted to determine whether DDAVP has an influence on the arousability of children with PNE. The children were tested under DDAVP and placebo conditions. Children were recruited through the enuresis clinics and those with a documented history of PNE were enrolled in the study. Physical examination, urinalysis, blood test and renal ultrasound were performed at the first visit. Eligible children were older than 6 years with monosymptomatic PNE, normal bladder capacity and a minimum of 2 wet nights a week for 2 consecutive weeks. Children with frequent urinary tract infections and urological or neurological abnormalities were excluded from study. No patient was allowed to take medication such as DDAVP or use conditioning therapy to treat PNE during the 3 months before study

Whole-genome and exome sequencing have already proven to be essential and powerful methods to identify genes responsible for simple Mendelian inherited disorders. These methods can be applied to complex disorders as well, and have been adopted as one of the current mainstream approaches in population genetics. These achievements have been made possible by next generation sequencing (NGS) technologies, which require substantial bioinformatics resources to analyze the dense and complex sequence data. The huge analytical burden of data from genome sequencing might be seen as a bottleneck slowing the publication of NGS papers at this time, especially in psychiatric genetics. We review the existing methods for processing NGS data, to place into context the rationale for the design of a computational resource. We describe our method, the Graphical Pipeline for Computational Genomics (GPCG), to perform the computational steps required to analyze NGS data. The GPCG implements flexible workflows for basic sequence alignment, sequence data quality control, single nucleotide polymorphism analysis, copy number variant identification, annotation, and visualization of results. These workflows cover all the analytical steps required for NGS data, from processing the raw reads to variant calling and annotation. The current version of the pipeline is freely available at http://pipeline.loni.ucla.edu. These applications of NGS analysis may gain clinical utility in the near future (e.g., identifying miRNA signatures in diseases) when the bioinformatics approach is made feasible. Taken together, the annotation tools and strategies that have been developed to retrieve information and test hypotheses about the functional role of variants present in the human genome will help to pinpoint the genetic risk factors for psychiatric disorders. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

Evidence is growing that monosymptomatic enuresis (ME) is a maturational disorder of the central nervous system with a lack of arousal and lacking inhibition of the micturition reflex. Previous studies have shown a significant reduction of prepulse inhibition (PPI) of startle in children with enuresis. However, it is still unclear whether the abnormal PPI in enuresis is based on an inhibitory deficit at brainstem or cortical level. Nine children with ME and ten healthy children were investigated using simultaneous recording of EMG from the M. orbicularis oculi and functional MRI. The experimental paradigm consisted of acoustic startle stimulation, with startle-alone stimuli and prepulse–startle combinations. Functional MRI data were processed using multiple regression and parametric modulation with startle amplitudes as a parameter. Neither patients with enuresis nor healthy children revealed measurable PPI in the MRI scanner. Startle stimuli caused equal hemodynamic changes in the acoustic cortex, medial prefrontal and orbitofrontal cortex in both groups. The amplitude of startle correlated with more prominent BOLD signal changes in the anterior cingulate cortex in healthy subjects than in patients with ME. This pronounced frontal activation in healthy controls was related to the PPI condition, indicating that the prefrontal cortex of healthy children was activated more strongly to inhibit startle than in patients with ME. In conclusion, apart from the possibility that recordings of PPI inside the MRI scanner may be compromised by methodological problems, the results of this study suggest that high cortical control mechanisms at the prefrontal level are relevant for the pathogenesis of ME.

Monosymptomatic enuresis (ME) is a common disorder in children with serious social and psychological consequences. Treatment is usually initiated with desamino-arginine vasopressin (dDAVP) and/or alarm therapy as first-line treatment and imipramine as second-line. All treatments have proven efficacy, but are not successful with all patients. Therefore, a differentiation into subgroups according to treatment efficacy would be beneficial.A group of patients resistant to first-line treatment was treated with imipramine and compared with matched controls successfully treated with dDAVP and/or alarm therapy. Prepulse inhibition (PPI) to acoustic startle reflexes was measured in all patients.In a group of 23 nonresponders, the median PPI was 72% (range 43-94%) compared with the matched dDAVP/alarm - responders with a median PPI of 26% (range 0-61%) (p0.0001). The response rate to imipramine was 87%.The presented data provide evidence that PPI allows to identify two subgroups of ME. The results offer further insight into (at least) two different pathomechanisms involved in ME: (i) a maturational delay of reflex inhibition with reduced PPI and (ii) a normal PPI, possibly with abnormal sleep patterns, that can be influenced by imipramine.

Despite the high prevalence of enuresis, the professional training of doctors in the evaluation and management of this condition is often minimal and/or inconsistent. Therefore, patient care is neither optimal nor efficient, which can have a profound impact on affected children and their families. Once comprehensive history taking and evaluation has eliminated daytime symptoms or comorbidities, monosymptomatic enuresis can be managed efficaciously in the majority of patients. Non-monosymptomatic enuresis is often a more complex condition; these patients may benefit from referral to specialty care centers. We outline two alternative strategies to determine the most appropriate course of care. The first is a basic assessment covering only the essential components of diagnostic investigation which can be carried out in one office visit. The second strategy includes several additional evaluations including completion of a voiding diary, which requires extra time during the initial consultation and two office visits before treatment or specialty referral is provided. This should yield greater success than first-line treatment. Conclusion: This guideline, endorsed by major international pediatric urology and nephrology societies, aims to equip a general pediatric practice in both primary and secondary care with simple yet comprehensive guidelines and practical tools (i.e., checklists, diary templates, and quick-reference flowcharts) for complete evaluation and successful treatment of enuresis.

Modern computational neuroscience employs diverse software tools and multidisciplinary expertise to analyze heterogeneous brain data. The classical problems of gathering meaningful data, fitting specific models, and discovering appropriate analysis and visualization tools give way to a new class of computational challenges--management of large and incongruous data, integration and interoperability of computational resources, and data provenance. We designed, implemented and validated a new paradigm for addressing these challenges in the neuroimaging field. Our solution is based on the LONI Pipeline environment [3], [4], a graphical workflow environment for constructing and executing complex data processing protocols. We developed study-design, database and visual language programming functionalities within the LONI Pipeline that enable the construction of complete, elaborate and robust graphical workflows for analyzing neuroimaging and other data. These workflows facilitate open sharing and communication of data and metadata, concrete processing protocols, result validation, and study replication among different investigators and research groups. The LONI Pipeline features include distributed grid-enabled infrastructure, virtualized execution environment, efficient integration, data provenance, validation and distribution of new computational tools, automated data format conversion, and an intuitive graphical user interface. We demonstrate the new LONI Pipeline features using large scale neuroimaging studies based on data from the International Consortium for Brain Mapping [5] and the Alzheimer's Disease Neuroimaging Initiative [6]. User guides, forums, instructions and downloads of the LONI Pipeline environment are available at http://pipeline.loni.ucla.edu.

Children with enuresis can be classified into those who wet their beds only at night (monosymptomatic enuresis, mE), and those who additionally suffer from daytime symptoms, such as urgency or incontinence (non-monosymptomatic enuresis, nmE). Evidence is growing that enuresis may have a central origin: bedwetting children have lower brainstem reflex control (impaired prepulse inhibition) than normal controls. However, findings on this subject are inconsistent. To date, there has been no study in pediatric patients according to the type of enuresis. With the aim of determining whether mE and nmE children differ in terms of central reflex control, we divided 30 enuretic children into two groups (mE and nmE) based on data recorded in a bladder diary and clinical history (19 with history of diurnal urge, 11 without; age 5–14 years). Prepulse inhibition (PPI) of the startle reflex of the children was measured and compared between groups. A significant difference in PPI was observed between the groups, with the nmE group having a lower median PPI level than the mE group (10 vs. 73%, respectively; p = 0.0002). These findings lead to the assumption that a loss of central control plays a role only in the etiology of nmE. Moreover, they may throw a new light on the classification of enuresis.

Udgivelsesdato: 2010-Feb PURPOSE: We provide updated, clinically useful recommendations for treating children with monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: Evidence was gathered from the literature and experience was gathered from the authors with priority given to evidence when present. The draft document was circulated among all members of the International Children's Continence Society as well as other relevant expert associations before completion. RESULTS: Available evidence suggests that children with monosymptomatic nocturnal enuresis could primarily be treated by a primary care physician or an adequately educated nurse. The mainstays of primary evaluation are a proper history and a voiding chart. The mainstays of primary therapy are bladder advice, the enuresis alarm and/or desmopressin. Therapy resistant cases should be handled by a specialist doctor. Among the recommended second line therapies are anticholinergics and in select cases imipramine. CONCLUSIONS: Enuresis in a child older than 5 years is not a trivial condition, and needs proper evaluation and treatment. This requires time but usually does not demand costly or invasive procedures.

Primary nocturnal enuresis (PNE) is a distressing condition, particularly in severe cases (or = 3 wet nights/week). A prevalent pathophysiological mechanism, especially in monosymptomatic PNE (PMNE), is commonly believed to be an insufficient increase in night-time release of antidiuretic hormone. Desmopressin, a synthetic analogue of antidiuretic hormone, has been shown to reduce the number of wet nights experienced by PMNE patients in several controlled trials.This study was performed to evaluate desmopressin treatment in the real-life clinical setting and was a large-scale, 6-month investigation of efficacy and safety in patients with severe PNE. Predictive factors for desmopressin response were also evaluated. A total of 744 children aged 5 years and above from four countries were involved in the study.At baseline, patients had a median of 6 wet nights/week; at 6 months, 41% of patients had experiencedor = 50% reduction in the mean number of wet nights. Long-term desmopressin treatment was consistently well-tolerated across all ages, with 5% of patients experiencing any treatment-related adverse events. The strength of treatment response was associated with nocturnal diuresis (p0.0001) and age (p = 0.0167) in logistic regression analyses. Compliance and dosage were also associated with response and more patients experiencedor = 50% reduction in wet nights after 6 months' treatment than earlier in the study, suggesting the value of persistent treatment.This study shows that long-term desmopressin treatment in the clinical setting is effective and well-tolerated in PNE patients of 5 years and upwards. Early improvements in bedwetting of any appreciable magnitude may be rewarding, may facilitate compliance and enable good long-term response.

The case of an 8 year old boy with both nocturnal enuresis and nephrogenic diabetes insipidus is presented. Diagnosis of nephrogenic diabetes insipidus was based on a typical medical history, the characteristic result of a fluid restriction test, the lack of an effect of 1-desamino-8-D-arginine (DDAVP) on both urine osmolality and plasma coagulation factors and, finally, the detection of a hemizygous missense mutation within the arginine vasopressin (AVP) receptor gene. Hydrochlorothiazide treatment and dietary measures reduced the patient's urine volume to one third of its original volume. However, this had no effect on enuresis. The daily intranasal application of DDAVP did not further reduce urine output but dramatically decreased the frequency of bed wetting. This observation contradicts the common notion that the therapeutic effect of DDAVP in nocturnal enuresis is the result of compensation for a nocturnal AVP deficit. Rather, it points to a different mode of action of DDAVP in patients with enuresis. It is hypothesised that central AVP receptors are a target of DDAVP and that they might play an important role in the pathogenesis of nocturnal enuresis.

Purpose: Studies of desmopressin in children with primary nocturnal enuresis show a greater than 90% decrease in wet nights in 20% to 30%, a 50% to less than 90% decrease in 20% to 40% and less than a 50% decrease in up to 60%. Insufficient response to desmopressin is attributable to various factors, including differences in the primary nocturnal enuresis definition, underlying bladder dysfunction and/or desmopressin pharmacokinetic characteristics. However, little attention has been given to poor compliance with therapy as a possible explanatory factor. For a drug with an effect duration limited to the night after administration a high degree of compliance is essential to ensure consistent therapeutic effects. Materials and Methods: This was a substudy of an international investigation of treatment for 6 months or less with desmopressin tablets in children with primary nocturnal enuresis. Medication was dispensed at each visit as required and collected at each subsequent visit. Compliance was determined by pill counts by study staff. Results: Compliance data were available on 723 patients. Of the patients 81% to 91% ingested all medication as instructed during the initial run-in phases. However, this decreased to 77% and 71% during the first and second 3-month treatment periods, respectively. Conclusions: Patient motivation and compliance are generally stronger in clinical trials than in clinical practice. However, this study shows that some patients were poorly compliant with medication even at study initiation and only 71% were fully compliant with long-term treatment. Decreased compliance was associated with a lower response rate. Patients should be encouraged to comply fully with treatment to achieve an optimal outcome.

Objective To test the hypothesis that 1-desamino-8-D-arginine vasopressin (dDAVP) has an effect on prepulse inhibition (PPI) of startle in patients with primary monosymptomatic enuresis (PME), thus indicating a central effect. Study design Patients with PME (n = 21, age 6 to 12 years) were enrolled in a prospective, randomized, double-blinded, cross-over study. Startle reflexes and PPI were measured under dDAVP treatment versus placebo. Results The data show that dDAVP has a significant effect on PPI, raising it from 38.88% under placebo to the age-related normal level of 62.6% with dDAVP treatment ( P = .0127). Conclusions Our findings revive the concept of a central pathophysiology of PME and offer a different explanation for the effects of dDAVP, which not only acts on the kidney, but also is (as is AVP) a central neurotransmitter with a signal cascade on relevant reflex mechanisms.

The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with ’renal glucosuria type 0′) were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m 2 /d (81 - 1120 mmol/1.73 m 2 /d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m 2 /d (24 mmol/1.73 m 2 /d). Likewise, in index cases with glucosuria below 10 g/1.73 m 2 /d (55 mmol/1.73 m 2 /d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance. E-mail: r.santer@uke.uni-hamburg.de

Treatment of primary nocturnal enuresis (PNE) using desmopressin (dDAVP) is based upon the hypothesis that antidiuretic hormone (arginine vasopressin (AVP) secretion is insufficient during the night. Persisting doubts about the theoretical background of this treatment gave reason to different studies: In a first study, AVP regulation in children with PNE was investigated. AVP levels after fluid restriction were compared to those of healthy controls. In order to maintain osmolality, the plasma AVP concentrations of the enuretic children rose to significant higher levels than in the controls. In a second study, the short-time memory of children treated with dDAVP because of PNE was measured. Children under dDAVP showed a significantly better short- time memory.The results are consistent with the established fact that AVP secretion is a function of plasma osmolality. They contradict the hypothesis that enuretic children have a AVP deficiency which has to be supplemented. Rather, the results point to central action of dDAVP, a defect at the central AVP receptor level or the signal transduction pathway.

Item does not contain fulltext We have investigated two unrelated families, in which two children had inherited primary nocturnal enuresis, and nephrogenic diabetes insipidus caused by new mutations in the aquaporin-2 gene (AQP2). The mutant AQP2 proteins were inactive, suggesting that administration of desmopressin could not concentrate the urine in these patients. However, treatment with desmopressin resolved primary nocturnal enuresis completely. This observation questions the notion that desmopressin resolves primary nocturnal enuresis through pharmacological manipulation of renal concentrating ability only. Desmopressin might also act on extrarenal targets such as the central nervous system. Muller, Dominik

Item does not contain fulltext BACKGROUND: The epithelial Ca(2+) channel (ECaC) exhibits the defining properties for being the gatekeeper in 1,25-dihydroxyvitamin D(3)-regulated Ca(2+) (re)absorption. Its recently cloned human orthologue (ECaC1) could, therefore, represent a crucial molecule in human disorders related to Ca(2+)-wasting such as idiopathic hypercalciuria (IH). METHODS: Fifty-seven members of nine families with IH were investigated. Phenotyping was performed by measurements of urinary Ca(2+) excretion, while other underlying disorders were appropriately excluded. Initially, the recently suggested locus for kidney stone-associated hypercalciuria on chromosome 1q23.3-q24 was investigated. Next, direct mutation analysis of all 15 exons of the ECAC1 gene and 2.9 kb upstream from the start codon was performed. hECaC1, heterologously expressed in human embryonic kidney 293 cells, was characterized by patch-clamp analysis. RESULTS: The mode of inheritance in the studied pedigrees is consistent with an autosomal dominant trait. Haplotype analysis did not implicate a role of the locus on chromosome 1. The coding sequence of the ECAC1 gene was not different between the affected and the non-affected family members. In the 5'-flanking region, three single nucleotide polymorphisms were encountered, but these polymorphisms were observed regardless of the affection status of the screened family members. Patch-clamp analysis of hECaC1 was performed as the putative pore region contains four non-conserved amino acid substitutions compared with the other species. This analysis revealed the distinctive properties of ECaC, including a high Ca(2+) selectivity, inward rectification, and Ca(2+)-dependent inactivation. CONCLUSION: These results do not support a primary role for hECaC1 in IH in nine affected families. Because of the heterogeneity of the disease, however, the involvement of ECaC1 in other subtypes of IH cannot be excluded and needs further investigation. The electrophysiological properties of hECaC1 further substantiate its prime role in Ca(2+) (re)absorption.

The use of desmopressin in patients with primary nocturnal enuresis is based on the hypothesis of a nocturnal lack of endogenous arginine vasopressin. However, in addition to the kidney, other targets of desmopressin are known. Therefore, we examined whether the administration of desmopressin influences central nervous function in children with primary nocturnal enuresis.Our prospective, randomized, double-blind, placebo controlled cross-over study was performed on 40 children with nocturnal enuresis. Patients were randomly assigned to receive either 20 microg. desmopressin intranasally or 0.9% saline solution. Each group comprised 19 and 21 to children, respectively. After 2 weeks the groups were switched. The children were tested for short-term memory and reaction time to both treatments. Statistical analysis was done using the Wilcoxon matched pairs test.Median patient age was 8.0 years (range 6 to 13). During desmopressin treatment children in both groups had a significant decrease of wet nights (5.3 to 3.2 per week). In contrast to reaction time, short-term memory was significantly different between both groups (p0.05).Our results demonstrate an increase in short-term memory after desmopressin treatment in children with nocturnal enuresis. This finding indicates the central nervous system as a target involved in the pathogenesis of nocturnal enuresis as well as the therapeutic benefit of desmopressin treatment.

Aesthetic autonomy versus biography: the 1930s and after T. S. Eliot famously argued in 'Tradition and the Individual Talent' (1919) for a perfect division between 'the man who suffers and the mind which creates'. Only thus could artists find the appropriate form for dealing with the problem or issue with which they were tussling; only thus would the necessary impersonality be achieved. In taking a very different path, D. H. Lawrence would pay a price but also find a rewarding freedom. Appreciating the implications of this changes one's understanding of virtually everything he wrote. Eliot’s desideratum articulated what would become a widely held cultural position. Contemporary reviewers and critics found indifference to Lawrence’s flouting of it impossible. Trenchant, occasionally vitriolic, disagreements resulted; and the dispute gave rise to nearly a dozen biographical studies in the decade after Lawrence’s death in 1930. In addition, many of the reviews of Lawrence’s posthumous publications, and essays and books about his whole oeuvre, took a biographical turn. John Middleton Murry staked out one side of the argument, and Catherine Carswell the other.

Item does not contain fulltext The prognosis of Henoch-Schonlein purpura (HSP) is mainly determined by the involvement of the kidney, but prognostic markers have not been established. To study the extent of tubular involvement in HSP and its relationship to the development of HSP nephritis, we measured the urinary excretion of two tubular marker proteins in 36 children with HSP. After admission, urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined in 20 children and alpha1-microglobulin (alpha1-MG) in 16 children respectively. These values were compared with the biochemical data on admission, 1 month, 6 months, and 12 months later. A total of 198 24-h urine samples from healthy children were used for the establishment of reference data for NAG and alpha1-MG (mean+/-2 SD). Twenty-one patients had elevated excretion of either NAG (>mean+2 SD, n=12) or alpha1-MG (>mean+2 SD, n=9). The highest values (>mean+4 SD) were found in patients with early kidney involvement. Normal values were accompanied by a benign further clinical course. Children with intermediate high values (>mean+2 SD

Functional and morphological analyses indicated that the epithelial Ca2+ channel (ECaC), which was recently cloned from rabbit kidney, exhibits the defining properties for being the gatekeeper in transcellular Ca2+ (re)absorption. Its human homologue provides, therefore, a molecular basis for achieving a better understanding of Ca2+ mal(re)absorption. By applying the RACE technique, the full-length cDNA of human ECaC (HGMW-approved symbol ECAC1) was obtained. It consisted of 2,772 bp with an open reading frame of 2,187 bp encoding a protein of 729 amino acids with a predicted molecular mass of 83 kDa. Phylogenetic analysis indicated that this highly selective Ca2+ channel exhibits a low level of homology (

Background.Treatment of primary nocturnal enuresis using 1-deamino-8-d-arginine-vasopressin is based on the hypothesis that antidiuretic hormone (arginine vasopressin [AVP]) secretion is insufficient during the night. Persisting doubts about the theoretical background of this treatment and first results pointing to a different AVP regulation in children with nocturnal enuresis were the motives for the present study.Objective.To determine if children with primary nocturnal enuresis have different AVP levels during fluid restriction when compared with normal controls.Methods.Twenty-three children with nocturnal enuresis (median age, 11 years) were compared with a corresponding control group of 18 healthy children. Plasma osmolality, urine osmolality, and plasma AVP concentrations were determined before and after a defined fluid restriction.Results.Regarding plasma and urine osmolality, no differences were found between the two groups. AVP levels after fluid restriction, however, showed significant differences. To maintain osmolality, the plasma AVP concentrations of the controls rose to a median value of 5.7 pg/mL (range: 0.9–29.0 pg/mL) in comparison to a median of 14.0 pg/mL (range: 3.5–64.0 pg/mL, P = .015) for the enuretic children.Conclusion.The results are consistent with the established fact that AVP secretion is a function of plasma osmolality. They contradict the hypothesis that enuretic children have a AVP deficiency that has to be supplemented. Rather, the results point to a defect at the AVP receptor level or of the signal transduction pathway.