Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-ß-catenin signaling. Constitutive activation of Wnt-ß-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

Adult and Pediatric Intra-Institutional Trends of Ciprofloxacin Susceptibility in E. coli Positive Urinary Cultures.

Antimicrobial drug resistance in treatment of urinary tract infection (UTI) continues to rise worldwide. To examine contributions of physician prescribing patterns to fluoroquinolone (ciprofloxacin, CP) resistance, we examined Escherichia coli (E. coli) resistance patterns in urinary cultures. Since CP usage is limited in children, we compared CP resistance trends in adults and children to those of more commonly used trimethoprim-sulfamethoxazole (TMP-SMX) and nitrofurantoin (NF). Our data show that although the general pediatric population has lower resistance to ciprofloxacin, resistance levels are rising with increased usage. While NF susceptibility is historically stable, TMP-SMX resistance is slightly higher in children compared to adults. In both adults and children, antimicrobial resistance patterns vary according to clinical practice site, with ambulatory urology patients showing the highest resistance. This suggests that physician's prescribing patterns contribute to antimicrobial resistance.

Three differentiation states risk-stratify bladder cancer into distinct subtypes.

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.

Trends in hospitalization for pediatric pyelonephritis: a population based study of California from 1985 to 2006.

PURPOSE: We examined trends in pediatric hospitalization for pyelonephritis from 1985 to 2006 and identified factors associated with admission. MATERIALS AND METHODS: We performed a population based analysis of hospital discharges using the Office of Statewide Health Planning and Development database to evaluate trends in California regarding pediatric hospitalizations for pyelonephritis from 1985 to 2006. Multivariable logistic regression was performed to identify factors associated with admission for pyelonephritis. RESULTS: A total of 46,300 children were hospitalized for pyelonephritis in California from 1985 to 2006. The overall rate of hospitalization for pyelonephritis increased by greater than 80%, from 17 per 100,000 children in the California population in 1985 to 31 per 100,000 in 2005. This change was primarily due to the nearly ninefold increase in pyelonephritis hospitalizations observed in children younger than 1 year, from 28 per 100,000 in 1985 to 238 per 100,000 in 2005. Among children younger than 1 year males without private insurance and of nonwhite race had increased odds of hospitalization, while females with private insurance and of Asian race had increased odds of hospitalization, compared with nonprivate insurance and white race, respectively. CONCLUSIONS: A significant increase in hospital admissions for pyelonephritis, primarily in children younger than 1 year, occurred in California between 1985 and 2006. Further studies are needed to establish the cause of this striking increase and to determine why certain pediatric populations are at increased risk for hospitalization.

Epidemiologic trends in penile anomalies and hypospadias in the state of California, 1985-2006.

PURPOSE: Using statewide data, we evaluated whether the changing incidence of penile anomalies and hypospadias is reflected in the diverse California population of newborn males over the past 20 years. METHODS: Discharge data from all California hospitals, prepared by the OSHPD (Sacramento, CA) was reviewed for the years 1985-2006 for male infant births with an ICD-9 code (752.6) for hypospadias, epispadias or other penile anomalies. Trends were examined by Generalized Estimation Equations for Poisson regression. RESULTS: From 1985 to 2006, the birth incidence of newborn penile anomalies increased in California from 47 to 57 cases per 10,000 newborn discharges, yet the trend for hypospadias alone appears stable from 1997. The rates for penile anomalies in newborns increased 1.4% annually (p < 0.001). All racial/ethnic groups analyzed showed this increase (p < 0.001 for each). During the study period there was a 2% increase per year in plural births (p < 0.001). Interestingly, the rate of change in penile anomaly incidence was greater in males of plural births compared to their singleton cohorts (2% vs 1% annually) (p < 0.001). The birth incidence of cleft palate, another congenital anomaly known to be stable over time, remained unchanged over this period. CONCLUSIONS: From 1985 to 2006 in California the incidence of penile anomalies increased in a statistically significant manner, but the incidence of hypospadias appears stable for the last decade. Our data support the notion that different racial/ethnic groups have distinct incidences of penile anomaly formation and that an association with plural births appears to be present.

Urinary tract infection in children: when to worry.

Urinary tract infection (UTI) is a frequent diagnosis in children who are referred to the urologist. Although most infections will resolve without complication after appropriate treatment, a wide array of potential complicating factors exists, which can make difficult the rapid resolution of a UTI. Clinical scenarios involving these factors require a high index of suspicion and prompt initiation of appropriate therapy.

Compliance with antibiotic prophylaxis in children with vesicoureteral reflux: results from a national pharmacy claims database.

PURPOSE: Antibiotic prophylaxis is commonly used for medical management of vesicoureteral reflux. Little information exists on compliance with antibiotic prophylaxis in patients with vesicoureteral reflux. MATERIALS AND METHODS: We queried the i3 Innovus (Ingenix) pharmacy claims 2002 to 2007 database for patients 18 years old or younger with vesicoureteral reflux (ICD-9 code 593.7 plus claim for cystogram) and analyzed those with at least 1 year of followup data. Criteria for management with antibiotic prophylaxis were 2 or more 30-day supplies of antibiotic prescriptions, or 4 or more 14-day supplies of prescriptions if the antibiotic was a penicillin or cephalosporin. Antibiotic prophylaxis compliance was determined using a medication possession ratio, an estimate of the proportion of time that patients have a prescribed drug available for use. Compliance was established as a medication possession ratio of 80% or greater, meaning coverage with antibiotic prophylaxis for 80% of the year or more. RESULTS: Of 9,496 patients with vesicoureteral reflux 5,342 (56.3%) were treated with antibiotic prophylaxis. Most patients were female (81%) and 5 years old or younger (79%). Trimethoprims/sulfonamides were most commonly prescribed (62%) and antiseptics were next (24%). Of patients prescribed antibiotic prophylaxis 40% were compliant. Compliance was lower for 6 to 10-year-olds (OR 0.71, 95% CI 0.61-0.83) and 11 to 18-year-olds (OR 0.56, 95% CI 0.41-0.79) compared to younger children (5 years or less). Increased compliance was associated with 1 or more hospitalizations (OR 1.70, 95% CI 1.48-1.97) and 1 or more urologist visits (OR 1.41, 95% CI 1.25-1.58). CONCLUSIONS: Among patients with vesicoureteral reflux who are prescribed prophylactic antibiotics 40% are compliant with treatment. Young age, frequent hospitalization and specialist visits are associated with compliance. This knowledge may help to develop effective interventions to improve compliance and underscores the importance of reporting compliance in clinical studies evaluating the usefulness of antibiotic prophylaxis in vesicoureteral reflux management.

Evaluation of asymptomatic, atraumatic hematuria in children and adults.

Asymptomatic, atraumatic hematuria is a worrisome clinical sign for a patient that usually prompts a visit to a urologist. Hematuria is classified as microscopic versus gross; the evaluation for gross hematuria differs from that for microscopic hematuria, and the most important differentiating factor is the patient's age. The major causes of hematuria differ between children and adults, and the evaluation should reflect this. Renal disease is more common in children and malignancy more common in adults. The application and utility of laboratory tests, radiological studies, and cystoscopy are well established in adults but are more variable in children. Follow-up of hematuria after a negative evaluation is becoming more limited in adults but should be routine for children.

The management of renal angiomyolipomas in a patient with tuberous sclerosis.

BACKGROUND: A 17-year-old girl, who was diagnosed with tuberous sclerosis in infancy, presented with multiple bilateral renal masses, the largest of which was 6.0 cm in diameter on the left side. INVESTIGATIONS: History and physical examination, ultrasonography, MRI, CT, magnetic resonance angiography, and measurement of serial creatinine levels. DIAGNOSIS: Bilateral angiomyolipomas.Management Observation, serial imaging, embolization and infarction.

Magnetic resonance imaging detected renal volume reduction in refluxing and nonrefluxing kidneys.

PURPOSE: Renal parenchymal damage is a well recognized sequela of urinary tract infection in the setting of vesicoureteral reflux. We investigated renal magnetic resonance imaging as a quantitative modality to detect renal parenchymal damage in children with primary vesicoureteral reflux and urinary tract infection. MATERIALS AND METHODS: We retrospectively reviewed the medical records of children with primary vesicoureteral reflux and urinary tract infection who underwent renal magnetic resonance imaging evaluation. Those with other genitourinary pathology were excluded. Controls underwent magnetic resonance imaging for nongenitourinary pathologies. Kidneys were segregated among control, nonrefluxing, and low grade (I to III) and high grade (IV to V) reflux. Size plots (magnetic resonance imaging volume vs age) were drawn for comparison. Gross imaging abnormalities observed were renal scarring and small size. RESULTS: Magnetic resonance imaging was performed in 114 patients with vesicoureteral reflux (228 kidneys, patient age 0.5 to 17.8 years) and 21 controls (42, 0.5 to 12). Higher grades of reflux were associated with smaller volume, and smaller volume was noted in the refluxing and nonrefluxing kidneys of children with vesicoureteral reflux. Kidneys from patients with unilateral or bilateral reflux had significantly decreased renal volume compared to controls (p <0.0001). Kidneys in which vesicoureteral reflux spontaneously resolved had renal volumes similar to control kidneys (p = 0.23). CONCLUSIONS: Use of magnetic resonance imaging derived renal volume allows renal comparison and is helpful in evaluating patients with vesicoureteral reflux. In patients with a history of a febrile urinary tract infection and reflux the finding of measurably smaller kidneys appears to be more common than scarring. Whether these findings represent renal atrophy or hypoplasia needs further investigation.

Pediatric urinary tract infections.

Pediatric urinary tract infections are common. These infections have been recognized as a source of acute morbidity and long-term medical consequences in adulthood. There are various risk factors and clinical presentations in children with urinary tract infections. The main objectives in management include prompt diagnosis, appropriate antimicrobial therapy, identification of anatomic anomalies, and, in select patients, long-term follow-up.

Hypnosis reduces distress and duration of an invasive medical procedure for children.

OBJECTIVE: Voiding cystourethrography (VCUG) is a commonly performed radiologic procedure in children that can be both painful and frightening. Given the distress that some children experience during the VCUG and the need for children to be alert and cooperative during the procedure, finding a psychological intervention that helps children to manage anxiety, distress, and pain is clearly desirable. This study was designed to examine whether relaxation and analgesia facilitated with hypnosis could reduce distress and procedure time for children who undergo this procedure. METHODS: Forty-four children who were scheduled for an upcoming VCUG were randomized to receive hypnosis (n = 21) or routine care (n = 23) while undergoing the procedure. The sample consisted of 29 (66%) girls and 15 (34%) boys with a mean age of 7.6 years (SD: 2.5; range: 4-15 years). Ethnic/racial backgrounds were 72.7% white, 18.2% Asian, 4.5% Latino, 2.3% black, and 2.3% Filipino. The mean number of previous VCUGs was 2.95 (SD: 2.51; mode: 2; range: 1-15). Potential participants were identified through computerized hospital records of upcoming VCUGs. Parents were contacted by telephone and invited to participate if their child was eligible. To be eligible for the study, the child must have undergone at least 1 previous VCUG, been at least 4 years of age at that time, and experienced distress during that procedure, and both the child and the participating parent had to be English speaking. Each eligible child and parent met with the research assistant (RA) before the day of the scheduled procedure for an initial assessment. Children were queried regarding the degree of crying, fear, and pain that they had experienced during their most recent VCUG. Parents completed a series of parallel questions. Immediately after this assessment, those who were randomized to the hypnosis condition were given a 1-hour training session in self-hypnotic visual imagery by a trained therapist. Parents and children were instructed to practice using the imaginative self-hypnosis procedure several times a day in preparation for the upcoming procedure. The therapist was also present during the procedure to conduct similar exercises with the child. The majority (83%) of those who were randomized to the routine care control group chose to participate in a hospital-provided recreation therapy program (offered as part of routine care). The program includes demonstration of the procedure with dolls, relaxation and breath work training, and assistance during the procedure. On the day of the VCUG, the RA met the family at the clinic before the procedure, and both the child and the parent rated the child's present level of fearfulness. During the procedure, the RA recorded observational ratings of the child's emotional tone and behavior and timed the overall procedure and its phases. Immediately after the VCUG, the child was asked how much crying, fear, and pain he or she had experienced during the procedure; the parent rated the child's experience on the same dimensions and also how traumatic the procedure had been (both generally and compared with their previous one), and the medical staff rated the degree of procedural difficulty. Outcomes included child reports of distress during the procedure, parent reports of how traumatic the present VCUG was compared with the previous one, observer ratings of distress during the procedure, medical staff reports of the difficulty of the procedure overall, and total procedural time. RESULTS: Results indicate significant benefits for the hypnosis group compared with the routine care group in the following 4 areas: (1) parents of children in the hypnosis group compared with those in the routine care group reported that the procedure was significantly less traumatic for their children compared with their previous VCUG procedure; (2) observational ratings of typical distress levels during the procedure were significantly lower for children in the hypnosis condition compared with those in the routine care condition; (3) medical staff reported a significant difference between groups in the overall difficulty of conducting the procedure, with less difficulty reported for the hypnosis group; and (4) total procedural time was significantly shorter-by almost 14 minutes-for the hypnosis group compared with the routine care group. Moderate to large effect sizes were obtained on each of these 4 outcomes. CONCLUSIONS: Hypnotic relaxation may provide a systematic method for improving the overall medical care of children with urinary tract abnormalities and may be beneficial for children who undergo other invasive medical procedures. Because the VCUG is an essential part of the evaluation of urinary tract infections and vesicoureteral reflux in children, lower distress during the procedure may improve patient and family compliance with initial as well as follow-up evaluations. These findings augment the accumulating literature demonstrating the benefits of using hypnosis to reduce distress in the pediatric setting. The present findings are noteworthy in that this study was a controlled, randomized trial conducted in a naturalistic medical setting. In this context, we achieved a convergence of subjective and objective outcomes with moderate to large effect sizes, including those that may have an impact on patient care and procedure cost, that were consistently supportive of the beneficial effects of hypnosis-a noninvasive intervention with minimal risk. The findings, therefore, have immediate implications for pediatric care. Limitations of this study include the lack of participant and staff blindness to the child's condition assignment, which could have introduced bias into reports. However, the objective procedural time differences between groups were consistent with the other, more subjective outcome findings. The sample was also small and primarily white in ethnic/racial makeup, which may have restricted our ability to detect some differences and may limit the generalizability of findings to more representative samples. In addition, the sample comprised children who had already undergone at least 1 VCUG during which they had had difficulty. Consequently, additional research is needed to determine whether hypnosis would be helpful to those who are undergoing their first VCUG. Additional limitations, clinical observations, and directions for future research are also discussed.

Laparoscopic Mitrofanoff appendicovesicostomy.

A novel technique of performing fully laparoscopic Mitrofanoff appendicovesicostomy in the management of neurogenic bladder is described. All steps, including appendix harvesting and extravesical appendiceal-vesical anastomosis with flap-valve mechanism creation, were completed laparoscopically and provided satisfactory preliminary clinical results. Additional studies are necessary for the evaluation of this novel technique.

Neuroblastoma: management, recurrence, and follow-up.

The clinical use of N-myc amplification in neuroblastoma management has served as a paradigm for "bench to bedside" medicine. It is hoped that the quest for molecular markers such as neurotrophin, TrkA, and TrkB will continue to advance the understanding of neuroblastoma. In addition, animal models of neuroblastoma (N-myc transgenic mice, and neuroblastoma xenografts) have been established to assess the efficacy of novel treatments. These advances are likely to improve clinical practice in the future.

Evaluation of renal growth by magnetic resonance imaging and computerized tomography volumes.

PURPOSE: Magnetic resonance imaging (MRI) and computerized tomography (CT) are commonly used to image complex medical conditions but limited data have been reported concerning normal renal volumetric measurement with these imaging techniques. We examined whether normative renal growth curves could be constructed from data derived from these imaging modalities, and from these curves assessed normal and abnormal renal development. MATERIALS AND METHODS: Patients who had undergone prior renal MRI or CT were identified. Total renal volume and renal cortical fraction (CF, cortical/total volume) were calculated, and growth curves were derived. To examine the curve utility for abnormal growth assessment, renal ultrasonography of children with reflux nephropathy was examined, and MRI and radionuclide scans were compared. RESULTS: A total of 60 patients 2 months to 39 years old who underwent MRI were included in the growth curve. The CF of the 120 kidneys was 75.8 +/- 4.3% and independent of sex and age. In 19 patients with vesicoureteral reflux 13 kidneys had cortical scarring, and the CF was decreased (p <0.001, 63.65 +/- 5.72%), indicating disproportionate cortical loss. No difference between CF for normal and vesicoureteral reflux unscarred kidneys was found. Differential renal function on radionuclide study correlated highly with MRI renal volume (r = 0.91). CT was performed in 70 children 1 to 15 years old (mean age 7.9) volume correlated with age and renal length, and the left kidney was larger than right kidney on MRI and CT. CONCLUSIONS: Normative renal growth curves can be constructed from CT and MRI derived renal volumes. Cortical fraction is consistent, and sex and age independent. In reflux nephropathy the CF is reduced and renal differential function on nuclear scan correlates with MRI derived differential volume. This concept may be useful for predicting abnormal renal growth and differential function.

Serial followup of the contralateral renal size in children with multicystic dysplastic kidney.

PURPOSE: Multicystic dysplastic kidneys have negligible renal function and the contralateral kidney (solitary kidney) frequently exhibits abnormalities that may affect growth. We previously showed that nomograms related to renal size constructed from digitalized ultrasonographic measurements of renal parenchymal area are a sensitive measure of renal growth and correlate with functional mass. We assess the age-dependent characteristics of compensatory renal growth in infants and children with multicystic dysplastic kidneys by construction of a growth curve for the contralateral kidney, assess these characteristics in comparison to normal renal growth of right and left kidneys, analyze the extent of compensatory renal growth and evaluate abnormal growth in solitary kidneys in infants and children. MATERIALS AND METHODS: From 1988 to 2000 we reviewed 152 serial sonograms from 48 patients with a diagnosis of multicystic dysplastic kidneys. We also reviewed 209 renal sonograms in patients whose studies, done for other purposes, showed normal bilateral kidneys. Using computer planimetry, parenchymal area and pelvicaliceal area were determined after digitalization of ultrasound images. Parenchymal area was calculated by parenchymal area minus pelvicaliceal area and expressed as a mean of 3 measurements. A parenchymal area growth curve was generated for the contralateral kidney in the multicystic dysplastic kidney group from birth to 216 months, and for right and left normal kidneys from birth to 338 months. Data were plotted as mean parenchymal area +/- 2 SD on a nomogram generated by linear regression. Differences in parenchymal area between normal right and left kidneys, between normal kidneys and the contralateral to multicystic dysplastic kidney were analyzed by unpaired Student t test. RESULTS: Of the 48 patients with multicystic dysplastic kidneys 36 had contralateral normal kidneys and 12 (25%) had a contralateral abnormality. Of the 12 cases 4 and an additional 5 without an identified abnormality (9 of 48) or 18.7% had solitary kidneys 2 SD below the normal growth curve for total parenchymal area, indicating a smaller than expected increase in compensatory renal growth. Conversely, 8 of 12 including 1 with grade V reflux into a solitary kidney exhibited normative compensatory renal growth. Left normal kidneys demonstrated a small but statistically significantly larger parenchymal area throughout growth. Solitary kidneys did not demonstrate growth differences associated with side. Solitary kidneys showed accelerated growth from 0 to 22 months while normal kidneys showed accelerated growth from 0 to 15 months. CONCLUSIONS: Nomograms constructed from ultrasonographic measurements of renal parenchymal area may be useful for assessing abnormal renal growth in solitary kidneys. Patients with solitary kidneys identified by conventional ultrasonographic measurement as normal may not exhibit expected growth. Clinical decision making may be improved by identification of solitary kidneys at risk for poor growth.