Richard S. Lee

Antenatal Hydronephrosis as a Predictor of Postnatal Outcome: A Meta-analysis

OBJECTIVE.Antenatal hydronephrosis is diagnosed in 1% to 5% of all pregnancies; however, the antenatal and postnatal management of hydronephrosis varies widely. No previous studies define the risk of postnatal pathology in infants with antenatal hydronephrosis. Our objective was to review the current literature to determine whether the degree of antenatal hydronephrosis and related antenatal ultrasound findings are associated with postnatal outcome. METHODS. We searched Medline (1966–2005), Embase (1991–2004), and the Cochrane Library databases for articles on antenatal hydronephrosis. We required studies to have subjects selected on the basis of documented measurements of antenatal hydronephrosis and followed to a postnatal diagnosis. We excluded case reports, review articles, and editorials. Two independent investigators extracted data. RESULTS. We screened 1645 citations, of which 17 studies met inclusion criteria. We created a data set of 1308 subjects. The risk of any postnatal pathology per degree of antenatal hydronephrosis was 11.9% for mild, 45.1% for moderate, and 88.3% for severe. There was a significant increase in risk per increasing degree of hydronephrosis. The risk of vesicoureteral reflux was similar for all degrees of antenatal hydronephrosis. CONCLUSIONS. The findings of this meta-analysis can potentially be used for prenatal counseling and may alter current postnatal management of children with antenatal hydronephrosis. Overall, children with any degree of antenatal hydronephrosis are at greater risk of postnatal pathology as compared with the normal population. Moderate and severe antenatal hydronephrosis have a significant risk of postnatal pathology, indicating that comprehensive postnatal diagnostic management should be performed. Mild antenatal hydronephrosis may carry a risk for postnatal pathology, but additional prospective studies are needed to determine the optimal management of these children. A well-defined prospective analysis is needed to further define the risk of pathology and the appropriate management protocols.

Pediatric Robot Assisted Laparoscopic Dismembered Pyeloplasty: Comparison With a Cohort of Open Surgery

PURPOSE We assessed the usefulness of RALP in children and compared an age matched cohort undergoing OPN to RALP for safety, efficacy, operative time, blood loss, in-hospital narcotic use and LOS. MATERIALS AND METHODS We performed a retrospective case-control study from 2000 to 2004 of 33 patients undergoing RALP and 33 undergoing OPN. Average age of each group was not significantly different (RALP 7.8 years vs OPN 7.6 years, p = 0.75). Mean followup of RALP and OPN groups was 10 and 21 months, respectively. RESULTS Etiology of the obstruction was not significantly different. Mean operative time was significantly less for OPN (181 minutes vs 219 minutes for RALP, p = 0.031). As RALP experience increased, operative times improved and approached the OPN experience. RALP complications included 1 patient requiring reoperative surgery vs no complications in the OPN group (p = 0.15). Patients undergoing RALP had a mean LOS of 2.3 days compared to 3.5 days for OPN (p <0.001). Total narcotic requirements were significantly less in the RALP group (p = 0.001). All patients in the OPN and 31 in the RALP group had either resolution of hydronephrosis, improvement in drainage or relief of symptoms. CONCLUSIONS We documented the safety and efficacy of RALP in children. RALP showed advantages of decreased hospital stay, decreased narcotic use and operative times approaching those of open surgery. RALP is an option for pyeloplasty, and as robotic technology improves, this method of repair may become the minimally invasive treatment of choice.

The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis

The evaluation and management of fetuses/children with antenatal hydronephrosis (ANH) poses a significant dilemma for the practitioner. Which patients require evaluation, intervention or observation? Though the literature is quite extensive, it is plagued with bias and conflicting data, creating much confusion as to the optimal care of patients with ANH. In this article, we summarized the literature and proposed recommendations for the evaluation and management of ANH.

Chronic Corticosterone Exposure Increases Expression and Decreases Deoxyribonucleic Acid Methylation of Fkbp5 in Mice

There is evidence for hypercortisolemia playing a role in the generation of psychiatric symptoms and for epigenetic variation within hypothalamic-pituitary-adrenal (HPA) axis genes mediating behavioral changes. We tested the hypothesis that expression changes would be induced in Fkbp5 and other HPA axis genes by chronic exposure to corticosterone and that these changes would occur through the epigenetic mechanism of loss or gain of DNA methylation (DNAm). We administered corticosterone (CORT) to C57BL/6J mice via their drinking water for 4 wk and tested for behavioral and physiological changes and changes in gene expression levels using RNA extracted from hippocampus, hypothalamus, and blood for the following HPA genes: Fkbp5, Nr3c1, Hsp90, Crh, and Crhr1. The CORT mice exhibited anxiety-like behavior in the elevated plus maze test. Chronic exposure to CORT also caused a significant decrease in the hippocampal and blood mRNA levels of Nr3c1 and a decrease in Hsp90 in blood and caused an increase in Fkbp5 for all tissues. Differences were seen in Fkbp5 methylation in hippocampus and hypothalamus. To isolate a single-cell type, we followed up with an HT-22 mouse hippocampal neuronal cell line exposed to CORT. After 7 d, we observed a 2.4-fold increase in Fkbp5 expression and a decrease in DNAm. In the CORT-treated mice, we also observed changes in blood DNAm in Fkbp5. Our results suggest DNAm plays a role in mediating effects of glucocorticoid exposure on Fkbp5 function, with potential consequences for behavior.

Family-based association of FKBP5 in bipolar disorder.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the α1 domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/−1.7 vs. 54.7 +/−3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

Nomograms for Predicting Annual Resolution Rate of Primary Vesicoureteral Reflux: Results From 2,462 Children

PURPOSE We determined the resolution rate of vesicoureteral reflux and the factors that influence it to formulate nomograms to predict the probability of annual resolution for individual cases of reflux. MATERIALS AND METHODS We studied 2,462 children with primary vesicoureteral reflux diagnosed between 1998 and 2006. Cox proportional hazards regression was used to model time to resolution as a function of statistically significant demographic and clinical variables. The resulting model was used to construct nomograms predicting the annual cumulative probability of reflux resolution. RESULTS Multivariate analysis showed that all cases of unilateral reflux resolved earlier than female bilateral reflux (HR 1.42, p <0.001). Additionally age less than 1 year at presentation (HR 1.31, p <0.001), lower reflux grade (2.96, p <0.001 for grade I; 2.28, p <0.001 for grade II; 1.63, p <0.001 for grade III), reflux diagnosed on postnatal evaluation for prenatal hydronephrosis or sibling screening (1.24, p = 0.002) and single ureter (1.55, p <0.001) were associated with significantly earlier resolution of reflux. Specific predicted cumulative probabilities of reflux resolution at annual intervals from diagnosis (1 to 5 years) were calculated for every possible combination of the significant variables. CONCLUSIONS Our analyses demonstrate that resolution of vesicoureteral reflux is dependent on age at presentation, gender, grade, laterality, mode of clinical presentation and ureteral anatomy. We constructed nomogram tables containing estimates of annual reflux resolution rate as a function of these variables. This information is valuable for clinical counseling and management decisions.

Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats

There is ample evidence that exposure to stress during gestation increases the risk of the offspring to develop mood disorders. Brain-derived neurotrophic factor (Bdnf) plays a critical role during neuronal development and is therefore a prime candidate to modulate neuronal signaling in adult offspring of rat dams that were stressed during gestation. In the current study, we tested the hypothesis that alterations in Bdnf expression in prenatally stressed (PNS) offspring are mediated by changes in DNA methylation in exons IV and VI of the Bdnf gene. We observed decreased Bdnf expression in the amygdala and hippocampus of prenatally stressed rats both at weaning and in adulthood. This decrease in Bdnf expression was accompanied by increased DNA methylation in Bdnf exon IV in the amygdala and hippocampus, suggesting that PNS-induced reduction in Bdnf expression may, at least in part, be mediated by increased DNA methylation of Bdnf exon IV. Expression of DNA methyltransferases (Dnmt) 1 and 3a was increased in PNS rats in the amygdala and hippocampus. Our data suggest that PNS induces decreases in Bdnf expression that may at least in part be mediated by increased DNA methylation of Bdnf exon IV.

Virtual quantification of metabolites by capillary electrophoresis-electrospray ionization-mass spectrometry: predicting ionization efficiency without chemical standards.

A major obstacle in metabolomics remains the identification and quantification of a large fraction of unknown metabolites in complex biological samples when purified standards are unavailable. Herein we introduce a multivariate strategy for de novo quantification of cationic/zwitterionic metabolites using capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) based on fundamental molecular, thermodynamic, and electrokinetic properties of an ion. Multivariate calibration was used to derive a quantitative relationship between the measured relative response factor (RRF) of polar metabolites with respect to four physicochemical properties associated with ion evaporation in ESI-MS, namely, molecular volume (MV), octanol-water distribution coefficient (log D), absolute mobility (mu(o)), and effective charge (z(eff)). Our studies revealed that a limited set of intrinsic solute properties can be used to predict the RRF of various classes of metabolites (e.g., amino acids, amines, peptides, acylcarnitines, nucleosides, etc.) with reasonable accuracy and robustness provided that an appropriate training set is validated and ion responses are normalized to an internal standard(s). The applicability of the multivariate model to quantify micromolar levels of metabolites spiked in red blood cell (RBC) lysates was also examined by CE-ESI-MS without significant matrix effects caused by involatile salts and/or major co-ion interferences. This work demonstrates the feasibility for virtual quantification of low-abundance metabolites and their isomers in real-world samples using physicochemical properties estimated by computer modeling, while providing deeper insight into the wide disparity of solute responses in ESI-MS. New strategies for predicting ionization efficiency in silico allow for rapid and semiquantitative analysis of newly discovered biomarkers and/or drug metabolites in metabolomics research when chemical standards do not exist.

Robot Assisted Laparoscopic Partial Nephrectomy: A Viable and Safe Option in Children

PURPOSE The safety, benefits and usefulness of laparoscopic partial nephrectomy have been demonstrated in the pediatric population. We describe our technique, and determine the safety and feasibility of robot assisted laparoscopic partial nephrectomy based on our initial experience. MATERIALS AND METHODS We retrospectively reviewed robot assisted laparoscopic partial nephrectomy performed at our institution between 2002 and 2005. The technique was conducted via a transperitoneal approach with the da Vinci Surgical System using standard laparoscopic procedural steps. Clinical indicators of outcomes included estimated blood loss, complications, in hospital narcotic use and length of stay. RESULTS Robot assisted laparoscopic partial nephrectomy was completed successfully in 9 cases. Mean patient age was 7.2 years and mean followup was 6 months. Mean operative time was 275 minutes and mean estimated blood loss was 49 ml. Operative times improved significantly with experience. Overall patients had a mean hospitalization of 2.9 days and required 1.3 mg morphine per kg. All patients had a normal remaining renal moiety confirmed on Doppler ultrasound. The only complication was an asymptomatic urinoma discovered on ultrasound, which was treated with percutaneous drainage and ultimately resolved. CONCLUSIONS Our initial experience shows the safety and feasibility of robot assisted laparoscopic partial nephrectomy in children. Operative time decreases with experience. The enhanced visualization and dexterity of a robotic system potentially offer improved efficiency and safety over standard laparoscopy. Robot assisted laparoscopy is an option for partial nephrectomy and may become the minimally invasive treatment of choice.