Frequency-specific alterations of the resting-state BOLD signals in nocturnal enuresis: an fMRI Study.

Resting state functional magnetic resonance imaging studies of nocturnal enuresis have focused primarily on regional metrics in the blood oxygen level dependent (BOLD) signal ranging from 0.01 to 0.08 Hz. However, it remains unclear how local metrics show in sub-frequency band. 129 children with nocturnal enuresis (NE) and 37 healthy controls were included in this study. The patients were diagnosed by the pediatricians in Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University School of Medicine, according to the criteria from International Children's Continence Society (ICCS). Questionnaires were used to evaluate the symptoms of enuresis and completed by the participants. In this study, fALFF, ReHo and PerAF were calculated within five different frequency bands: typical band (0.01-0.08 Hz), slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), slow-3 (0.073-0.198 Hz), and slow-2 (0.198-0.25 Hz). In the typical band, ReHo increased in the left insula and the right thalamus, while fALFF decreased in the right insula in children with NE. Besides, PerAF was increased in the right middle temporal gyrus in these children. The results regarding ReHo, fALFF and PerAF in the typical band was similar to those in slow-5 band, respectively. A correlation was found between the PerAF value of the right middle temporal gyrus and scores of the urinary intention-related wakefulness. Results in other bands were either negative or in white matter. NE children might have abnormal intrinsic neural oscillations mainly on slow-5 bands.

Adenotonsillectomy Normalizes Hormones and Urinary Electrolytes in Children With Nocturnal Enuresis and Sleep-Disordered Breathing.

OBJECTIVE: To assess (1) plasma levels of antidiuretic hormone (ADH) and brain natriuretic peptide (BNP) and urinary levels of electrolytes in children with sleep disordered breathing (SDB), with or without nocturnal enuresis (NE), and (2) the effect of adenotonsillectomy (T&A) on urinary electrolytes and the secretion of ADH and BNP in children with NE and SDB. We previously reported post-T&A improvements in plasma levels of BNP and ADH in children with SDB and NE. However, the differences in plasma concentration of these hormones in SDB children with and without NE, and their relationships with urinary electrolytes, have not yet been addressed. METHODS: This prospective study compared concentrations of urinary electrolytes and plasma ADH and BNP in (1) children with SDB and NE (study group) and an age- and sex-matched control group of children with SDB without NE, and (2) the study group before and 1-month after T&A. RESULTS: Compared with the control group (n = 31), the study group (n = 37) exhibited significantly lower ADH (P = .04) and higher BNP (P = .009) plasma levels. The differences in urinary electrolytes were not significant. Post-T&A, the study group showed significantly decreased BNP (P = .018), urinary sodium-to-creatinine ratio (P = .02), and urinary calcium-to-creatinine ratio (P = .007) compared with the pre-T&A values. Post-T&A changes in urinary calcium were significantly correlated with changes in sodium excretion (P = .002) and in plasma levels of BNP (P <.001). CONCLUSION: The presence of NE is associated with altered ADH and BNP levels in children with SDB. T&A led to normalization of ADH and BNP, probably through a calcium- and sodium-dependent mechanism.

Can urinary nerve growth factor and bladder wall thickness correlation in children have a potential role to predict the outcome of non-monosymptomatic nocturnal enuresis?

INTRODUCTION: Measurement of bladder wall thickness (BWTh) by ultrasound has been introduced as a new and promising technique to assess bladder dysfunction, and increased levels of nerve growth factor have also been reported in the bladder tissue and urine of patients with sensory urgency and detrusor overactivity (DO). OBJECTIVE: In this study we aimed to generate a clinically useful tool with urinary nerve growth factor levels and ultrasonographic BWTh to find possible pathogenetic clues and prognostic indicators as guides for the choice of therapy of non-monosymptomatic nocturnal enuresis. METHODS: A total of 110 children, aged 6-16 years old, were involved in this prospective study. Group 1 consisted of children with non-monosymptomatic nocturnal enuresis (n = 40), Group 2 of children with monosymptomatic nocturnal enuresis (n = 40) and Group 3 of children with healthy normal controls (n = 30). Children were evaluated with detailed history and physical examination, including neurologic examination; they were asked to complete a self-reported questionnaire and a 3-day bladder diary with the aid of their parents. The number of wet nights, the number of voids per night, the presence of daytime voiding symptoms (urgency, urge incontinence, incontinence, holding maneuvers, frequency), fluid intake, and any history of urinary tract infections (UTIs) were recorded. Monosymptomatic nocturnal enuresis and non-monosymptomatic nocturnal enuresis diagnosis was made using the International Children's Continence Society definition. Urinary nerve growth factor levels were measured by enzyme-linked immunosorbent assay and BWTh was measured transabdominally by a uroradiologist who specialized in pediatric ultrasonography. Urinary nerve growth factor levels were normalized by urinary creatinine levels and compared in all subgroups. RESULTS: The mean age of the study group was 9.6 (range 6-16) years. The mean BWTh was significantly increased in Group 1 compared with Group 2 (4.33 ± 1.12 mm, 2.33 ± 1.03 mm; p < 0.001) and healthy controls (4.33 ± 1.12 mm, 1.86 ± 0.57 mm; p < 0.001, respectively). Urinary levels of nerve growth factor corrected to urine creatinine (NGF/Cr) significantly increased in Group 1 with to Group 2 (2.75 ± 1.15 vs. 0.58 ± 0.15; p < 0.001) and controls (2.75 ± 1.15 vs.0.28 ± 0.10; p < 0.001, respectively). In receiver operating characteristic analysis, BWTh was found to have sensitivity of 95% and specificity of 85.7% (3.00 area under the curve [AUC] 0.937; 95%) and NGF/Cr had sensitivity of 97.5% and specificity of 98.6% (0.885; AUC, 999; 95%) in predicting lower urinary tract symptoms (LUTS) for non-monosymptomatic nocturnal enuresis (NMNE) (Figure). DISCUSSION: In our study we have investigated that BWTh together with urinary NGF levels normalized to the concentration of urinary creatinine (NGF/Cr) may predict daytime voiding problems in children with primary nocturnal enuresis (PNE). The main basis of this study is previous findings which demonstrated that ultrasonography (US)-based measurement of BWTh is a useful diagnostic parameter for LUTS in children, and that increased levels of NGF in bladder tissue and urine such as sensory urgency, DO, and overactive bladder (OAB) was indicated by clinical and experimental studies. The present study demonstrated that urinary NGF/Cr levels and BWTh measurements were significantly increased in patients with NMNE with daytime urinary symptoms (urgency, urge-incontinence, incontinence, frequency) showing symptoms of an OAB than controls and MNE. CONCLUSION: BWTh measurements and NGF/Cr values, as non-invasive tools, may guide therapy and improve outcomes in the treatment of children with NMNE. Further studies including a larger number of patients would be of great interest.

Brain metabolite alterations in children with primary nocturnal enuresis using proton magnetic resonance spectroscopy.

Nocturnal enuresis is a common developmental disorder in children; primary monosymptomatic nocturnal enuresis (PMNE) is the dominant subtype. Previous literature has suggested that the prefrontal cortex and the pons are both involved in micturition control. This study aimed to investigate the metabolic levels of the left prefrontal cortex and the pons in children with PMNE by proton magnetic resonance spectroscopy (1H-MRS). Twenty-five children with PMNE and 25 healthy children took part in our experiments. Magnetic resonance examinations were performed on a Siemens 3T Trio Tim scanner. For each subject, localized 1H-MRS was acquired from the left prefrontal cortex (mainly in brodmann area 9) and the pons with a point-resolved spectroscopy sequence with repetition time 2,000 ms, echo time 30 ms and 64 averages. The LCModel software package was used to analyze the MRS raw data, and two-sample t tests were used to determine significant differences between the two groups. The results revealed a significant reduction in metabolite to total creatine ratios of N-acetylaspartate (NAA/tCr) in the left prefrontal cortex and the pons for children with PMNE compared to healthy children. Our study suggests that metabolism is disturbed in the prefrontal cortex and the pons in children with PMNE, which may be associated with the symptoms of enuresis.

Anti-diuretic hormone and genetic study in primary nocturnal enuresis.

OBJECTIVE: To investigate whether primary nocturnal enuresis (PNE) is related to a disturbance in anti-diuretic hormone (ADH) secretion pattern at night which may be genetically inherited. SUBJECTS AND METHODS: This study included 121 children aged 6-18 years with PNE and 45 matched healthy children as controls. Enuretic children were subjected to genetic evaluation and cytogenetic assessment (n = 99). Assay of ADH levels (9-11 am & 9-11 pm) was performed for cases (n = 99) and controls. RESULTS: There was a positive family history in 82.4% (autosomal dominant in 35.4% and autosomal recessive in 64.6%). ADH morning and evening values were reversed in cases vs controls with significant difference in morning level. Reversal of circadian rhythm was present in 71.7% of cases and normal rhythm in 28.3% of them. Morning and evening ADH levels revealed significant difference between patients with reversed rhythm and those with normal one, and with controls. Mode of inheritance had no influence on hormonal level. Chromosomal abnormality was detected in 3 cases with reversed ADH rhythm, involving chromosome 22 in two of them. CONCLUSION: PNE could be attributed in part to reversed ADH circadian rhythm which may be linked to chromosome 22.

Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm.

Nocturnal enuresis in children and nocturia in the elderly are two highly prevalent clinical conditions characterized by a mismatch between urine production rate in the kidneys and storage in the urinary bladder during the sleep phase. Here we demonstrate, using a novel method for automated recording of mouse micturition, that connexin43, a bladder gap junction protein, is a negative regulator of functional bladder capacity. Bladder connexin43 levels and functional capacity show circadian oscillations in wild-type mice, but such rhythms are completely lost in Cry-null mice having a dysfunctional biological clock. Bladder muscle cells have an internal clock, and show oscillations of connexin43 and gap junction function. A clock regulator, Rev-erbα, upregulates connexin43 transcription as a cofactor of Sp1, using Sp1 cis-elements of the promoter. Therefore, circadian oscillation of connexin43 is associated with the biological clock and contributes to diurnal changes in bladder capacity, which avoids disturbance of sleep by micturition.

Recent patenting activities in the discovery and development of vasopressin V2 receptor agonists.

INTRODUCTION: Vasopressin V(2) agonists are well known as effective therapies in the treatment of central diabetes insipidus and nocturnal enuresis. Furthermore, given their mode of action, these particular agonists have more recently been considered, in both the pharmaceutical industry and in academia, as viable therapies for urological conditions such as nocturia. AREAS COVERED: For the past 10 years, significant progress has been made in the discovery and development of vasopressin V(2) agonists. This article provides the reader with information on the recent progress in the discovery and development of these compounds based on patents published from 2002 onward. Specifically, the article looks at the discovery of new non-peptide agonists as well as well as novel formulations of the vasopressin V(2) agonist desmopressin. EXPERT OPINION: The V(2) receptor is currently one of the hottest therapeutic targets investigated for the treatment of urinary disorders such as nocturia and central diabetes. Over the past 10 years, significant progress has been made in the discovery and development of vasopressin V(2) receptor agonists, for the treatment of these disorders. The author anticipates that these agonists will be launched to market in the not-too-distant future.

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.

Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults.

The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.

Nocturnal polyuria in monosymptomatic nocturnal enuresis refractory to desmopressin treatment.

The transition from day to night is associated with a pronounced decline in diuresis with reductions in the amount of excreted water, electrolytes, and other end products of our metabolism. Failure to do so leads to a large urine output at night, a condition known as nocturnal polyuria, encountered in a large proportion of children with nocturnal enuresis. The aim of this study was to clarify the mechanisms responsible for the nocturnal polyuria seen in enuretics with inadequate response to desmopressin (dDAVP). Forty-six enuretics (7-14 yr of age) and fifteen age-matched controls were admitted for a 24-h protocol with standardized fluid and sodium intake, comprising urine collections, blood sampling, and blood pressure monitoring. We included patients with severe enuresis (5 +/- 1 wet nights/wk) showing <50% reduction in wet nights on dDAVP. We characterized the patients on the basis of their nocturnal urine production. The children with nocturnal polyuria excreted larger amounts of sodium and urea at night than nonpolyurics and controls. Solute-free water reabsorption as well as urinary arginine vasopressin and aquaporin-2 excretion were normal in polyurics, and no differences were found in atrial natriuretic peptide, angiotensin II, aldosterone, and renin levels. Urinary prostaglandin E2 (PGE2) excretion was significantly higher in polyurics. The nocturnal polyuria in children with dDAVP-resistant nocturnal enuresis seems to be the result of augmented sodium and urea excretion. The high urinary PGE2 levels found in these children point toward a role for increased prostaglandin synthesis in the pathogenesis of enuresis-related polyuria.