Do repeat ultrasounds affect orchiectomy rate in patients with testicular torsion treated at a pediatric institution?

INTRODUCTION: Testicular torsion is a urological emergency; as the testicular salvage rate decreases with time, prompt intervention is required to restore the blood flow. Interhospital transfers and ultrasound examinations, while clinically essential to proper treatment and diagnosis, may adversely affect outcomes by delaying surgical intervention. Patients transferred to another institution for treatment of testicular torsion may experience a further time delay by undergoing two ultrasound examinations: one at the initial admitting institution and one at the receiving institution. To the knowledge of the authors, no study has yet explored the time delays and outcomes associated with these repeat ultrasounds. OBJECTIVE: The objective was to investigate the impact of repeat ultrasound imaging on time to treatment and patient outcomes in patients with testicular torsion. STUDY DESIGN: A retrospective chart review of 133 patients, aged 0-20 years, treated at the authors' institution for testicular torsion was conducted. Neonate patients and patients who did not receive ultrasound were excluded. Demographic and clinical variables were collected from the electronic medical record. Pearson Chi-squared and t-tests were used for univariate comparisons, and multivariate logistic regression analysis was performed to measure the relationships between variables. RESULTS: Forty-nine percent of patients were primary patients, and 51% were transfer patients. Fifty-two percent of transfer patients received repeat ultrasounds. In comparison to salvaged patients, those who underwent orchiectomy experienced a greater delay between presentation at the institution and surgical intervention (229 min vs 177 min, p = 0.048). The transfer status does not appear to be related to the outcome, i.e. orchiectomy versus salvage. Patients who underwent orchiectomy were more likely than salvaged patients to have received repeat ultrasounds (p = 0.008). Repeat ultrasound patients had three times the likelihood of orchiectomy of single ultrasound patients. In a subset analysis of transfer patients, repeat ultrasound patients were more likely than single ultrasound patients to receive an orchiectomy (p = 0.03). DISCUSSION: In agreement with previous studies, patients who underwent orchiectomy were found to experience greater treatment delays and trend toward transfer. Specifically, repeat ultrasound and time between presentation and intervention appear to influence patient outcomes. The effect of repeat ultrasound on outcomes appears to be independent of the transfer status. The study was limited by its retrospective nature and small sample size. CONCLUSION: The analysis suggests that efforts to prevent repeat ultrasounds and minimize the time between presentation and intervention would improve patient outcomes. It is proposed that standardized clinical decision-making procedures, such as the TWIST scoring system, be incorporated into hospital protocols.

Interdisciplinary pain management is beneficial for refractory orchialgia in children.

INTRODUCTION: Idiopathic testicular/groin pain can be a difficult entity for children, their families, and caregivers. The role of interdisciplinary pain management has previously been demonstrated in treating chronic orchialgia at the present pediatric pain clinic. OBJECTIVE: To evaluate the role of interdisciplinary pain management in managing refractory orchialgia. It was hypothesized that children with refractory orchialgia might respond well. Interdisciplinary care was defined as that which crosses two medical disciplines such as a surgical specialty and specialist in analgesia. SUBJECTS AND METHODS: Pediatric patients were identified who were: ≥ 10 years old; evaluated in the pediatric urology clinic between 2002 and 2012; were diagnosed wtih ICD code 608.9 or had the diagnosis of male genital disorder NOS. Children were included if they presented with orchialgia without an identifiable cause and failed conservative management (rest, scrotal support, Sitz bath, timed voiding, constipation avoidance) including conventional anti-nociceptive analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids). Patient electronic medical records were reviewed retrospectively. RESULTS: Twenty-two children met inclusion criteria. Mean age was 13.7 years (range 10-17). Nearly half (45%) of the children had chronic medical conditions such as asthma, allergies, and obesity. Twenty-one of the 22 children were referred to the pediatric pain clinic; 15 were evaluated, and one refused treatment. All children evaluated in the pediatric pain clinic were initially offered an empiric anti-neuropathic anti-convulsant (i.e. gabapentin) and/or an anti-depressant (i.e. amitriptyline) before being offered a nerve block. Of the 14 children accepting treatment in the pediatric pain clinic, six were treated solely with an empiric anti-neuropathic anti-convulsant and/or anti-depressant; eight received medications followed by nerve block (seven ilioinguinal-iliohypogastric blocks, one spinal and ilioinguinal-iliohypogastric block) (see Fig. 1). A total of eight of the 14 children (57%) treated by the pain clinic had resolution of pain, with 50% of those treated with medications alone (three out of six children) responding (two responding to gabapentin and a tricyclic antidepressant, one to gabapentin alone); and five out of eight (63%) treated with medications and then nerve block (ilioinguinal-iliohypogastric block) responding. Of the eight children undergoing nerve block, five required more than one block. The time between each block ranged from 4 to 22.6 weeks. Response to nerve block required an average of 1.4 procedures (range 1-2); mean follow-up after nerve block was 2.4 months (range 0.1-4.8). DISCUSSION: Children with refractory orchialgia often have comorbidities that suggest a multidisciplinary approach would be useful for treating them. The present study found that the majority of children with refractory orchialgia treated in the pediatric pain clinic responded to management. Major limitations, however, included small cohort size and short follow-up, particularly in those children undergoing nerve block. There was also no objective assessment of pain improvement or improvement in quality of life, which could be rectified with a prospective study. CONCLUSION: Collaboration and early referral for interdisciplinary pain management as one of these multidisciplinary approaches may help to coordinate care and ease patient suffering.

First stage approximation of the exstrophic bladder in patients with cloacal exstrophy--should this be the initial surgical approach in all patients?

PURPOSE: Cloacal exstrophy is rare and it represents a reconstructive challenge. Options for managing the urinary tract include primary closure or approximation of the bladder halves in the midline with later closure. We present our observations and evolving thoughts concerning optimal treatment in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with cloacal exstrophy seen in the last 5 years. Initial management was examined, including complete primary closure vs a staged approach. We noted midline defects, spinal cord abnormalities or other anatomical reasons that precluded primary closure. RESULTS: Seven patients, including 5 females and 2 males, were identified. An omphalocele noted in all 7 patients was closed in 5 at initial operation. All underwent preservation of the hindgut in the fecal stream. Spinal cord tethering was noted in 7 of 7 cases. Complete primary bladder closure was performed in 3 of the 7 patients, while the size of the bladder plates or a large abdominal wall defect precluded closure in the remainder. Continence was not achieved in the 3 cases closed primarily. All patients achieving urinary continence underwent bladder neck closure and augmentation cystoplasty with a continent catheterizable channel. CONCLUSIONS: Patients with cloacal exstrophy have anatomical issues that can prevent complete primary bladder closure or preclude the achievement of urinary continence. The high incidence of tethered cord places these patients at risk for upper tract changes and bladder decompensation during followup. Despite successful primary closure in 3 of 7 patients all have a tiny bladder and require secondary procedures to become continent. Extensive dissection during the first operation can contribute to more difficult dissection with potential increased morbidity during subsequent surgeries. Therefore, the best initial approach for the typical patient may be closure of the abdominal wall and approximation of the exstrophied bladder halves in the midline. Secondary closure with continent diversion and reconstruction of the external genitalia can be performed at ages 18 to 24 months.

Continent catheterizable channels and the timing of their complications.

PURPOSE: We reviewed our experience with continent catheterizable channels with interest in the timing of conduit related complications. MATERIALS AND METHODS: A retrospective review was performed of the outcome of continent catheterizable channels in all patients between 1998 and 2003 who had undergone construction of an antegrade continence enema and/or a Mitrofanoff procedure using appendix, small bowel or continent cutaneous vesicostomy. We performed a total of 117 such stomas in 37 male and 41 female patients 2.5 to 20 years old (mean age 8.9). For the antegrade continence enema we used appendix in 92% of cases, an ileal Yang-Monti tube in 6% and a cecal tube in 2%. For the continent catheterizable channel we used appendix in 43% of cases, a Yang-Monti tube in 38% and continent cutaneous vesicostomy in 19%. RESULTS: Continence was achieved in 98% of patients. Followup was 6 to 71 months (mean 28.4). There were 27 channel related complications (23%). Stomal stenosis occurred in 7 antegrade continence enema procedures (14%) within 1 to 10 months (mean 6.2) and in 9 continent bladder channels (13%), including 5 continent cutaneous vesicostomies, within 1 to 24 months (mean 9.4) after surgery. False passages occurred in 5 antegrade continence enema procedures (10%) within 1 to 13 months (mean 3.6) and in 4 continent catheterizable channels (6%) within 1 to 13 months (mean 6.5) after surgery. Of patients with stomal stenosis 50% were treated with surgical revision, while the remainder was successfully treated with dilation. Most false passages were managed by catheter drainage alone. Reasons for revision were contained perforation, colovesical fistula and inability to catheterize. Patient noncompliance appeared to have a role in stomal stenosis. CONCLUSIONS: Continent catheterizable stomas help patients achieve bowel and bladder continence. Stomal incontinence after reconstruction is rare. In our experience most stoma related complications occurred in the first year after reconstruction. Experience with more patients and longer followup will help determine whether such problems continue to accumulate with time or whether continent stomas function well with time, particularly after the initial period of healing.

Management of the failed pyeloplasty: a contemporary review.

PURPOSE: We reviewed our experience with open dismembered pyeloplasty, with specific focus on the presentation and management of failed pyeloplasty in the pediatric population. MATERIALS AND METHODS: We performed a retrospective review of patients who had undergone open dismembered pyeloplasty between 1998 and 2003. All patients with less than 6 months of followup were excluded from analysis. The patients were followed postoperatively with serial ultrasounds, with renograms reserved for those patients with prolonged, persistent or worsening hydronephrosis, or recurrent symptoms during followup. RESULTS: A total of 105 pyeloplasties were performed in 103 patients (71 males and 32 females) 1 to 204 months old (mean 60), with an overall success rate of 93.3%. Followup ranged from 6 to 69 months (mean 23). The 7 patients with treatment failure were males 1 to 204 months old (mean 125), who presented most commonly with pain within 3 to 38 months (mean 13.1) after initial surgery. Subsequent ultrasound revealed worsening hydronephrosis, and renography in these patients showed a pattern consistent with obstruction. Five patients underwent initial balloon dilation, in which 1 was successful. In addition, 1 of these patients underwent an unsuccessful antegrade laser endopyelotomy. Six patients (86%) underwent open surgery, consisting of ureterocalicostomy in 3 and reoperative dismembered pyeloplasty in 3. Dense scarring was seen in all patients, 2 patients had a redundant pelvis causing kinking and 2 patients had unrecognized crossing vessels. Overall salvage rate was 100% with continued followup of 3 to 50 months (mean 18). CONCLUSIONS: Dismembered pyeloplasty was successful in the vast majority of patients. In our series failures occurred as late as 3 years postoperatively, although most presented within 12 months of followup. Excluding routine postoperative nuclear renography did not seem to affect our ability to identify these cases. Although anatomical features such as renal pelvic size may have a role, failure is most likely secondary to technical issues, including missed crossing vessels and dependency of the anastomosis. In this series failed pyeloplasties did not respond well to balloon dilation, likely due to scar formation. Our current practice is to manage failures by open surgery, although endoscopic management by an incision may be an option.

Proteomic method for the quantification of methionine sulfoxide.

Glycoxidation and lipoxidation reactions contribute to the chemical modification of proteins during the Maillard reaction. Reactive oxygen species, produced during the oxidation of sugars and lipids in these processes, irreversibly oxidize proteins. Methionine is particularly susceptible to oxidation, yielding the oxidation product methionine sulfoxide (MetSO). Here we describe a method for the analysis of MetSO using proteomic techniques. Using these techniques, we measured MetSO formation on the model protein RNase during aerobic incubations with glucose and arachidonate. We also evaluated the susceptibility of MetSO to reduction by NaBH4), a commonly used reductant in the analysis of Maillard reaction products.

Mass spectrometric analysis of glucose-modified ribonuclease.

RNase A (1 mM) was incubated with glucose (0.4 M) at 37 degrees C for up to 14 days in phosphate buffer (0.2 M, pH 7.4), digested with trypsin and analysed by LC-MS. The major sites of fructoselysine formation were Lys(1), Lys(7), Lys(37) and Lys(41). Three of these sites (Lys(7), Lys(37) and Lys(41)) were also the major sites of N epsilon-(carboxymethyl)lysine formation.

Is postoperative cystography necessary after ureteral reimplantation?

OBJECTIVES: To evaluate the patients in our practice to determine whether postoperative cystography was useful in monitoring the outcome after ureteroneocystostomy. Surgical repair of vesicoureteral reflux is the treatment of choice after medical therapy failure. Radiographic evaluation by ultrasonography or voiding cystourethrography (VCUG) is commonly used postoperatively to evaluate for urinary tract obstruction or persistent reflux. However, imaging modalities are not without cost, both in monetary terms and in terms of radiation exposure and trauma to the child. METHODS: We reviewed the records of all patients who underwent ureteroneocystostomy without ureteral tapering at our institution between January 1, 1996 and December 31, 1999 for primary vesicoureteral reflux. These records were evaluated with respect to the type of surgical procedure, preoperative and postoperative clinical course, and radiographic studies performed. RESULTS: We performed reimplantation on 267 renal units in 153 patients. The surgical technique was the Cohen cross-trigonal in 120 renal units (45%), Glenn-Anderson ureteral advancement in 92 (35%), and modified Leadbetter-Politano ureteral advancement in 55 (20%). All patients underwent imaging with ultrasonography within 6 weeks of surgery. The follow-up ranged from 4 to 42 months (average 14.2). Between 3 and 8 months postoperatively, 61 patients underwent imaging with VCUG. We identified persistent reflux in six renal units. Four of six had marked improvement in their reflux. All the patients with persistent reflux were asymptomatic, including 2 patients who were no longer receiving antibiotics. Four patients developed febrile urinary tract infections postoperatively. Three of the four underwent imaging with VCUG after treatment; all three had no evidence of reflux. CONCLUSIONS: In our population, the addition of VCUG to the postoperative evaluation did not allow us to identify those patients at risk of febrile urinary tract infections. Patients in whom persistent reflux was identified were all asymptomatic. We continue to monitor patients with ultrasonography, but believe that VCUG often provides little benefit to these children.

Early evolution of bladder emptying after myelomeningocele closure.

OBJECTIVES: To analyze bladder emptying in newborns with spina bifida after closure of the myelomeningocele defect. Manipulation of the spinal cord and nerve roots results in temporary changes in bladder function in many settings. METHODS: We reviewed 62 consecutive newborn patients who underwent closure of a myelomeningocele defect at our institution from January 1990 to December 1997. We examined the catheterized urine volumes obtained before and after closure, radiographic and urodynamic studies, and the subsequent need for intermittent catheterization. Poor bladder emptying was defined as most catheterized urine volumes greater than 10 mL (20% of expected bladder capacity). Adequate follow-up was available for 54 patients for a period of 4 to 96 months (mean 42). One patient with posterior urethral valves was excluded from the study, leaving 53 for evaluation. RESULTS: Of the 53 patients, 4 with high outflow resistance and dyssynergy never emptied the bladder adequately before or after closure. Of the remaining 49 patients, 6 (12%) emptied well immediately after the myelomeningocele repair. In the other 43 (88%), the bladder did not empty as well after closure. The mean volume obtained with catheterization after closure was 20 mL, significantly higher (P <0.001) than the mean volume obtained before repair (6.5 mL) or after resumption of better spontaneous emptying (4 mL). Intermittent catheterization done for poor emptying was required for an average duration of 11 days (range 2 to 42). Of the 43 patients with poor emptying immediately after closure, 32 (74%) required catheterization for 2 weeks or less; the remaining 11 (26%) required catheterization for 2 to 6 weeks. Despite the relatively early resumption of good emptying, numerous patients (19 of 49) required additional intervention (clean intermittent catheterization or vesicostomy) before attempts to toilet train. CONCLUSIONS: A clinical pattern similar to spinal shock does occur in most newborns after closure of a myelomeningocele defect. Resumption of near-complete emptying usually occurs less than 2 weeks after repair but may require up to 6 weeks.

Angiotensin type II receptor expression and ureteral budding.

PURPOSE: Deletion of the angiotensin type II receptor gene (Agtr2) in mice results in a spectrum of urinary tract anomalies similar to that in humans. The mechanism behind this anomalous development is poorly understood. We evaluated Agtr2 expression as it relates to normal and abnormal ureteral budding. MATERIALS AND METHODS: A total of 400 wild type mice were inspected at birth for gross evidence of a urinary tract anomaly. In addition, the urinary tracts of 30 wild type embryos were evaluated at 11.0/11.5 and 13.5 weeks of gestation. These embryos were examined for ureteral budding site via section and whole mount in situ hybridization with c-ret probe and Agtr2 expression via in situ hybridization with Agtr2 riboprobe. There were 740 newborn mice homozygous for the null mutation of Agtr2 also evaluated along with 55 angiotensin type II knockout embryos at the aforementioned gestational ages. RESULTS: All wild type newborn animals were grossly normal. Of the angiotensin type II knockout newborns 23 (3.1%) had gross abnormalities of the urinary tract at birth. The predominant finding was a duplicated collecting system associated with a hydronephrotic upper pole moiety. These duplicated collecting systems fulfilled the Meyer-Weigert law. Interestingly, 25 (59.5%) of the knockout embryos showed abnormal ureteral budding. However, in wild type embryos Agtr2 was expressed at this "ectopic" cranial site between the wolffian duct and metanephric mesenchyme. CONCLUSIONS: Although not the sole regulator, angiotensin type II receptor expression may have a role in the embryological development of the urinary tract by inhibiting aberrant ureteral budding. A defect in this inhibitory process appears to cause ectopic ureteral budding, and may subsequently lead to renal dysplasia and other congenital anomalies of the kidney and urinary tract.

Measurement of bisphenol A levels in human urine.

We report a new approach for assessing human exposure to bisphenol A (BPA) by measuring BPA in urine after enzymatic deglucuronidation. This method involves addition of (13)C(12)-labeled BPA, enzymatic deconjugation, solid-phase extraction, and derivatization with pentafluorobenzyl bromide. The product of the derivatization is separated by gas chromatography followed by mass spectrometric detection using negative chemical ionization and selected ion monitoring. Using this analysis method, urine samples fortified with both a constant level of labeled BPA and a range of unlabeled BPA levels (0.27-10.6 ng/ml) demonstrated constant percentage recovery. In addition, a range of urine sample volumes (0.25-10.0 ml) with constant amounts of added internal standard produced a linear response (r(2)=0.99). The method limit of detection was 0.12 ng/ml. This method was validated by duplicate analyses using gas chromatography coupled to a high-resolution mass spectrometer.

Exposure to persistent organochlorines among Alaska Native women.

OBJECTIVES: To report the levels of DDT, DDE, other chlorinated pesticides, and PCBs found in 131 Alaska Native women who had serum samples collected between 1980 and 1987 and to compare these levels to other published studies of DDE and PCB exposure among U.S. women. STUDY DESIGN: Review of data collected during a case-control study of the relationship between organochlorine chemicals and breast cancer. Data for case and control women were pooled in this analysis because case-control differences were found to be minimal and because serum samples pre-dated cancer diagnoses by 3 to 10 years. RESULTS: More than 99% of the women had detectable levels of p,p-DDE (mean 9.10 ng/mL or ppb). Mean total PCB level was 7.56 ppb. Levels of exposure varied by geographical location and ethnic identification, which maybe a reflection of dietary differences. Five of the organochlorines were detected in at least half of the study population. Results were recalculated using detection limits corresponding to other published studies of DDE and PCB levels in U.S. women. Alaska women had levels similar to those reported from New York women collected in the 1980s. We compared the PCB congener levels measured in Alaska Native women with levels reported in Arctic animals and found similar PCB congener profiles. The six most frequently detected contaminants in Alaska Natives were also detected in the marine mammal samples reported by Becker et al (5). CONCLUSIONS: Our study identified widespread Alaska Native exposure to organochlorines that originated outside of the Arctic, a finding also seen in other studies. Our results provide a reference baseline for exposure levels during the 1980s, but further research is necessary to assess temporal trends in exposure among Alaska Natives. Further, the need for national and international inter-laboratory standardization for testing for persistent organochlorines to facilitate comparisons between Alaska Natives and other American populations is clearly demonstrated.

Association between maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth.

BACKGROUND: DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) is highly effective against most malaria-transmitting mosquitoes and is being widely used in malaria-endemic areas. The metabolite, DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has been linked to preterm birth in small studies, but these findings are inconclusive. Our aim was to investigate the association between DDE exposure and preterm birth. METHODS: Our study was based on the US Collaborative Perinatal Project (CPP). From this study we selected a subset of more than 44000 eligible children born between 1959 and 1966 and measured the DDE concentration in their mothers' serum samples stored during pregnancy. Complete data were available for 2380 children, of whom 361 were born preterm and 221 were small-for-gestational age. FINDINGS: The median maternal DDE concentration was 25 mg/L (range 3-178)-several fold higher than current US concentrations. The adjusted odds ratios (OR) of preterm birth increased steadily with increasing concentrations of serum DDE (ORs=1, 1.5, 1.6, 2.5, 3.1; trend p<0.0001). Adjusted odds of small-for-gestational-age also increased, but less consistently (ORs=1, 1.9, 1.7, 1.6, 2.6; trend p=0.04). After excluding preterm births, the association of DDE with small-for-gestational-age remained. INTERPRETATION: The findings strongly suggest that DDT use increases preterm births, which is a major contributor to infant mortality. If this association is causal, it should be included in any assessment of the costs and benefits of vector control with DDT.

Small intestinal submucosa as a urethral coverage layer.

PURPOSE: Urethrocutaneous fistula is the most common complication of hypospadias surgery. Numerous techniques have been used to decrease the incidence of this complication and the use of biocompatible materials in surgery has expanded the options in difficult situations. We hypothesized that porcine small intestinal submucosa may be used as a coverage layer after urethral surgery. We evaluated the histological changes associated with small intestinal submucosa when used as a coverage layer over the urethra in a rabbit model. METHODS AND METHODS: We performed urethral surgery in 16 New Zealand White rabbits divided into 4 animals each in groups 1-sham operation with penile degloving only, 2-penile degloving and small intestinal submucosa patch placement, 3-urethrotomy without a patch and 4-urethrotomy with a small intestinal submucosa patch. The graft edges were marked with permanent suture at surgery for later identification. All rabbits were maintained for 6 weeks before sacrifice. The urethra of each animal was then serially sectioned and examined histologically. RESULTS: Histological examination of animals with an small intestinal submucosa patch revealed a foreign body tissue reaction with an infiltrate of histiocytes, giant cells and lymphocytes in the area of graft placement. There was no histological evidence of remaining small intestinal submucosa patch in any sections. The urethral mucosa healed normally in all cases in which it was disrupted. There was no evidence of acute or chronic inflammation in any group 1 or 2 nonsmall intestinal submucosa animals and none in the animals with a small intestinal submucosa graft in areas other than the former graft site. There were also no urethrocutaneous fistulas in any of the 8 rabbits that underwent urethrotomy. CONCLUSIONS: Small intestine submucosa provides an adequate coverage layer in the rabbit penis after urethrotomy. Histologically the foreign material did not alter normal healing of the urethral mucosa, although it did appear to cause an infiltration of histiocytes, giant cells and lymphocytes. Small intestinal submucosa has previously been studied as a scaffold on which tissue may be remodeled or may regenerate. Our study shows that small intestinal submucosa did not interfere with normal tissue healing in this animal model. When used as a urethral coverage layer, it appears to provide extra tissue between the urethra and skin. Small intestinal submucosa may potentially decrease the incidence of urethrocutaneous fistula after urethral surgery.

Polychlorinated biphenyl serum levels in pregnant subjects with diabetes.

OBJECTIVE: Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain; detectable amounts are in the blood of nearly everyone. Their effect on humans at background levels of exposure is an area of active investigation. Increased blood levels of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin), a PCB-like compound, have recently been reported among subjects with diabetes, suggesting that PCB levels could be similarly elevated. To test this hypothesis, we examined a group of pregnant women whose serum PCB levels had been measured and whose diabetes status had been previously recorded. RESEARCH DESIGN AND METHODS: Using stored serum from a large birth cohort study, we conducted a cross-sectional study of 2,245 pregnant women, of whom 44 had diabetes (primarily type 1) and 2,201 were control subjects. RESULTS: The adjusted mean serum level of PCBs among the subjects with diabetes was 30% higher than in the control subjects (P = 0.0002), and the relationship of PCB level to adjusted odds of diabetes was linear. CONCLUSIONS: The possibility exists that PCBs and diabetes are causality related; alternatively, the pharmacokinetics of PCBs could be altered among patients with diabetes. At any event, if the association is replicated in other studies, increased serum levels of PCBs in subjects with diabetes or their offspring may put them at increased risk of PCB-induced changes in thyroid metabolism or neurodevelopment.

Congenital anomalies of the kidney and urinary tract--role of the loss of function mutation in the pluripotent angiotensin type 2 receptor gene.

PURPOSE: Recent studies of the human genome and genetic engineering experiments in mice revealed that congenital anomalies of the kidney and urinary tract commonly seen in newborns in various anatomical forms are polygenic disease, that is a disease caused by simultaneous defects in multiple genes. We discuss some possible genetic explanations of the classic theories of the formation of congenital kidney and urinary tract anomalies. MATERIALS AND METHODS: We reviewed classic and current theories regarding urinary tract development. Included in our review are recent results from our laboratory evaluating the genetic role of normal and abnormal urinary tract development. RESULTS: We observed a genetic abnormality that may explain many classic anatomical theories of congenital kidney and urinary tract anomalies. One of the genes involved in urinary tract ontogenesis is the angiotensin type 2 receptor gene, which is the "other" angiotensin receptor. While the type 1 receptor mediates essentially all known actions of angiotensin, including its hypertensive effect, relatively little is known about the angiotensin type 2 receptor. Careful dissection studies in mutant mouse embryos selectively lacking the angiotensin type 2 receptor gene revealed that this gene is pleiotropic, that is its defect causes not only ectopic ureteral budding from the wolffian duct, but also disturbance in other subsequent ontogenic events that are critical for the normal growth of the kidney and urinary tract. CONCLUSIONS: Many congenital anomalies of the kidney and urinary tract appear to share a common genetic cause. While these anomalies are caused by various genetic hits, abnormalities in the angiotensin type 2 receptor gene are often involved in this anomalous development. This review article offers a better understanding of the genetics involved in urinary tract development and ties some of the newly emerging genetic theories with classic anatomical theories.

The use of radiography, urodynamic studies and cystoscopy in the evaluation of voiding dysfunction.

PURPOSE: Children with dysfunctional voiding disorder often undergo radiological, cystoscopic or urodynamic evaluation to identify an anatomical or organic cause. We determined the role of these studies in the evaluation, management and ultimate outcome of a large patient population with voiding dysfunction at a single institution. MATERIALS AND METHODS: We retrospectively evaluated the records of 1, 153 children with dysfunctional voiding disorder treated from 1990 to 1999. A thorough history and physical examination with specific emphasis on voiding patterns were done and urinalysis was performed in all cases. Ultrasound of the urinary system and excretory urography were done in 1,050 (91%) and 24 (2%) patients, respectively, while voiding cystourethrography was performed in 672 (58%), including 564 with a history of nonfebrile urinary tract infection. Cystoscopy and a formal urodynamic study were performed in 61 (5%) and 40 (3.5%) cases, respectively. RESULTS: Mean patient age at referral was 6 years (range 3 to 14). Of the children 74% were girls and 26% were boys. Physical examination of the abdomen, back, genitalia and neurological system was unremarkable in all cases. Ultrasound of the upper urinary system was normal in 1,018 patients (97%) and showed insignificant pyelectasis in 32 (3%). All 24 excretory urography studies were normal and voiding cystourethrography was normal in 470 of 672 cases (70%). Unilateral and bilateral low grade, and unilateral high grade reflux was present in 108, 19 and 3 patients, respectively. Urodynamic studies were performed in 40 children who did not respond to standard treatment. We noted detrusor instability in 16 patients, detrusor-sphincter dyssynergia in 6 and sensory abnormality in 3, while the study was completely normal in 10. Cystoscopy revealed normal findings in 17 cases, trabeculations in 21, inflammation in 20 and type 1 posterior urethral valves in 2. CONCLUSIONS: The incidence of upper tract changes and positive anatomical findings in children with voiding dysfunction is too low to justify routine radiological evaluation and cystoscopy. However, in those who present with a nonfebrile urinary tract infection there remains an important role for voiding cystourethrography. We do not recommend routine urodynamics in children with voiding disorder because this study does not change therapy or influence the final outcome. Thorough history and physical examination lead to the correct diagnosis and treatment in the majority of children. A focus on correcting faulty voiding behavior with the judicious administration of antibiotics and anticholinergic therapy leads to a favorable outcome in most cases.

K-ras and p53 in pancreatic cancer: association with medical history, histopathology, and environmental exposures in a population-based study.

Pancreatic cancer is a highly fatal cancer with few identified risk factors. Increased risk of pancreatic cancer in tobacco smokers and among diabetic patients is well established, and some reports have suggested associations with coffee consumption and occupational exposure to organochlorines. At present, there is little information regarding the possible association of these risk factors with the known genetic alterations found in pancreatic cancers, such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor gene. Knowledge of such relationships may help to understand the molecular pathways of pancreatic tumorigenesis. We investigated the association between these molecular defects and risk factors for pancreatic cancer in 61 newly diagnosed patients identified through an ongoing study of pancreatic cancer in the San Francisco Bay Area. Interview information was obtained regarding environmental exposures, medical history, and demographic factors. Serum levels of dichlorodiphenyltrichloroethylene (DDE) and polychlorinated biphenyls were available on a subset of 24 patients. Tumor blocks were located from local hospitals and used for K-ras mutational analysis at codon 12 and for p53 protein immunohistochemistry. The molecular analyses were facilitated through the use of laser capture microdissection, which provides a reliable method to obtain almost pure populations of tumor cells. Mutations in K-ras codon 12 were found in 46 (75%) of 61 pancreatic cancers. A prior diagnosis of diabetes was significantly associated with K-ras negative tumors (P = 0.002, Fisher's exact test). The absence of this mutation was also associated with increased serum levels of DDE, although this association was not statistically significant (P = 0.16, Wilcoxon's test). There was no difference in polychlorinated biphenyl levels between the K-ras wild-type and mutant groups. Immunohistochemical staining for p53 protein did not differ by patient characteristics or clinical history, but significant associations were found with poor glandular differentiation (P = 0.002, chi2 trend test), severe nuclear atypia (P = 0.0007, chi2 trend test), and high tumor grade (P = 0.004, chi2 trend test). Our results are suggestive of the presence of K-ras codon 12 mutation-independent tumorigenesis pathways in patients with prior diabetes and possibly in patients with higher serum levels of DDE. Our results also support a role for the p53 tumor suppressor protein in the maintenance of genomic integrity.