Aneuploidy: a report of an ECETOC task force.

Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell aneuploidy activity may then be considered; aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.

Splanchnic artery pseudo-aneurysms secondary to blunt abdominal trauma in children.

Traumatic splanchnic artery pseudo-aneurysms are uncommon; only two cases have been reported among the pediatric population. The authors describe their experience with four patients in whom splanchnic artery pseudoaneurysms developed after blunt abdominal trauma. Splenic artery pseudo-aneurysms were found in a 6-year-old boy and an 8-year-old girl after blunt splenic injuries. In both cases, spontaneous thrombosis of the pseudo-aneurysms occurred after a period of observation. Hepatic artery pseudoaneurysms were found in a 7-year-old boy and a 10-year-old girl after major liver lacerations. The boy had successful angiographic embolization of the lesion, but the girl required direct ligation of the pseudo-aneurysm after nearly exsanguinating from acute hemorrhage. All four children have recovered completely, with no long-term sequelae. Traumatic splanchnic artery pseudo-aneurysms are potentially life-threatening complications that can occur after blunt abdominal trauma. The investigation and management of these lesions must be individualized according to the clinical scenario.

Voiding cystourethrography in children with urinary tract infection: the frequency of vesicoureteric reflux is independent of the specialty of the physician requesting the study.

OBJECTIVE: The purpose of this study was to determine if the frequency of vesicoureteric reflux on voiding cystourethrography in children with a history of urinary tract infection varies according to the specialty of the physician requesting the examination. MATERIALS AND METHODS: The study included 309 children (192 girls, 117 boys) with a history of urinary tract infection who had their first voiding cystourethrogram. The median age at first voiding cystourethrogram in boys was 12 months; in girls, it was 48 months. The reports of these examinations were retrospectively reviewed, and the presence of vesicoureteric reflux was recorded. The age and sex distribution of children referred for voiding cystourethrography by pediatric urologists and nephrologists (subspecialists) was compared with the age and sex distribution of children referred by pediatricians, family practitioners, and adult urologists (other clinicians). The rate of detection of vesicoureteric reflux was calculated according to age and sex. Ages studied were younger than 1 year, younger than 2 years, 2-4 years, and 5 years or older. The frequency of vesicoureteric reflux in children referred by subspecialists was compared with the frequency in children referred by other clinicians, allowing for the age and sex of the children. RESULTS: The sex distribution of children referred for voiding cystourethrography was similar for subspecialists and other clinicians. More children younger than 2 years old were referred by other clinicians than by subspecialists. Vesicoureteric reflux was found in 30% of boys and 29% of girls. The frequency of reflux in boys did not change with age. The frequency of reflux in girls 5 years or older (15%) was less than in younger girls. We found no significant difference between the rates of reflux in boys and girls within the age groups examined. The overall rate of detection of reflux in patients referred by subspecialists (30%) was almost the same as that in patients referred by other clinicians (29%). We also found no difference in the frequency of reflux in children referred by subspecialists compared with children referred by other clinicians after allowing for the age and sex of the children. CONCLUSION: In children with a history of urinary tract infection, the rate of detection of vesicoureteric reflux on voiding cystourethrography is independent of the specialty of the physician requesting the examination.

Polypropylene production and colorectal cancer: a review of the epidemiological evidence.

Polypropylene has been produced for over 35 years and has a wide variety of applications including industrial uses, food packaging and many domestic uses. As a high-molecular-weight polymer, polypropylene is considered chemically inert with little or no physiological or toxicological effects. Nevertheless, early epidemiological studies of polypropylene production workers and carpet manufacturing employees who use polypropylene reported a significant excess of colorectal cancer. In one study, five of the seven cases were diagnosed within a five-month period, and in the other study, five cases were diagnosed within an 18-month period. Recent updates of these two study populations have found no continuation of the excess of colorectal cancer, thereby indicating that the earlier observations on these two groups reflected the chance nature of a time-space cluster. Moreover, investigations of polypropylene production workers in the United States, Germany, Australia and the United Kingdom found no association with colorectal cancer. When the results of all studies of polypropylene production workers are pooled, the summary risk ratio for colorectal cancer is 1.37 (95% confidence interval 0.83-2.11). Taken together, the epidemiological evidence and the absence of toxicological data do not support a causal association between polypropylene and colorectal cancer.

Pathology considerations for, and subsequent risk assessment of, chemicals identified as immunosuppressive in routine toxicology.

Several proposals have been made with the aim of assisting in the early identification of chemicals with immunotoxic potential. The Organisation for Economic Cooperation and Development is now likely to incorporate enhanced immunopathology into the test guideline for the 28-day rat study, which may be regarded as a Tier I investigation. However, no guidelines have yet been proposed either for how the new data generated will be evaluated, or for how a subsequent risk assessment will be made. In this paper, considerations for the immunopathological assessment of the thymus, spleen, lymph nodes and bone marrow are described, together with comments on haematological and organ weight changes that may be associated with immunotoxicity. Their interpretation will depend on the doses at which changes are manifest, the quantity and quality of the effects observed and the presence and severity of other forms of toxicity. Lastly, risk assessment and the approach to Tier II testing in immunotoxicity is discussed. It is concluded that much of this work must be on a case-by-case basis, but should not in principle differ from the approach adopted for any other type of toxicity identified ina 28-day study.

Prepubertal ovarian cyst formation: 5 years' experience.

OBJECTIVE: To document the frequency of ovarian cyst formation in the prepubertal female and to report on the clinical implications of these cysts. METHODS: We evaluated cases from a retrospective chart review of prepubertal females with ovarian cysts. RESULTS: Over a 5-year period, 1818 ultrasound studies were completed in prepubertal females, from which 99 patients were identified as having ovarian cysts. The majority (82 of 99, 83%) were small, unilocular cysts averaging 2-3 mm in diameter. The incidence of these small cysts ranged at 2-5% in females between birth and age 8. Large ovarian cysts (ie, greater than 2 cm in diameter) are rare in young girls over age 2, with most occurring within the first year of life. Of the 17 large ovarian cysts, two presented with torsion and both were complex on ultrasound examination. Five (29%) of the large ovarian cysts were treated conservatively and demonstrated regression on follow-up; these were unilocular cysts. Although functioning cysts resulting in precocious pseudopuberty are expected to be rare, we identified five cases (5%) in our series. CONCLUSIONS: Small, unilocular ovarian cysts less than 1 cm in diameter are found in prepubertal females with a frequency of 2-5% and are clinically insignificant. Ovarian cysts greater than 2 cm are rare. Unilocular ovarian cysts less than 5 cm may be followed conservatively with ultrasound surveillance until regression, without a major risk of torsion. Ovarian cysts associated with precocious pseudopuberty are generally larger than 2 cm and may be recurrent.

Long term survival of an infant with sirenomelia.

We report on a 3-month-old infant whose sirenomelia was diagnosed prenatally. The infant is neurologically normal and has "fusion" of the lower limbs with associated renal dysplasia, imperforate anus, pelvic and sacral "dysplasia," and genital abnormalities. In addition she has a preauricular skin tag and rib fusion. The infant's anomalies are compatible with life and surgical separation of the lower limbs is planned.

New concepts in imaging of the gastrointestinal tract in children.

This article highlights some of the significant recent advances in imaging of the pediatric gastrointestinal tract that have occurred over the last decade. The current roles of the newer imaging modalities, including ultrasound, computed tomography, and magnetic resonance imaging, are discussed and illustrated. Particular emphasis is given to antenatal evaluation, suspected gastric outlet obstruction, inflammation, and other causes of the acute abdomen. Enhancements in fluoroscopic techniques are outlined, including the use of the newer contrast agents as well as air reduction of intussusception. Continued good communication between the pediatric radiologist and pediatric surgeon is vital to improve the care to children with disorders of the gastrointestinal tract.

Cardiac rhabdomyomata and megacystis-microcolon-intestinal hypoperistalsis syndrome.

Multiple cardiac rhabdomyomata were discovered on necropsy tissue review of a previously well child with megacystis-microcolon-intestinal hypoperistalsis syndrome, who died unexpectedly at home at 40 months of age. Multiple cardiac rhabdomyomata occur rarely and have not previously been reported with this syndrome. They are most frequently associated with tuberous sclerosis. The finding of multiple cardiac rhabdomyomata in this patient suggests the possibility that these two rare conditions may be associated. Putative gene loci for tuberous sclerosis have been assigned to the long arms of chromosomes 9 and 11 and it is possible that the cardiac rhabdomyomata seen in this patient are a serendipitous indicator of the location of the megacystis-microcolon-intestinal hypoperistalsis gene.

Intussusception: barium or air?

At The Hospital For Sick Children, the use of air has recently replaced the use of barium in the reduction of intussusceptions. The purpose of this study was to review the results from 200 consecutive patients with intussusceptions, 100 patients treated with barium enema and 100 patients treated with air enema. The groups were similar with regard to sex, average and median ages, and presenting symptoms and signs. Successful reduction was achieved in 75% of episodes of intussusception treated with barium enema and 76% treated with air enema. Failure of either modality showed a high association with the presence of either a lead point or an ileoileal or ileoileocolic intussusception. Among those cases of unsuccessful reduction, operation was performed in all 59 cases; resection in 30 cases, manual reduction in 19, and spontaneous reduction was found in 10. There were three perforations during attempted reduction with barium and two with air. All perforations were treated by resection and primary anastomosis. There were 18 recurrent intussusceptions following barium enema reduction and nine following air enema reduction. Therefore, with the lower absorption of x-rays by air and the relatively inert nature of air (compared with barium in the event of a perforation), we feel that air enema is the treatment of choice in the initial management of intussusception.

Simple renal cysts in children: diagnosis and follow-up with US.

To assess the sonographic frequency of simple renal cysts in children, the authors retrospectively reviewed the results of abdominal sonographic studies of 16,102 children performed over a 5-year period between January 1, 1985, and December 31, 1989. Patients with abnormal renal function, dysplastic kidneys, or a family history of polycystic kidney disease were excluded from the study. The authors' review of the sonograms revealed 37 simple cysts in 35 patients (0.22%); the cysts were evenly distributed by age and sex and measured from 0.3 to 7.0 cm in maximum diameter. Sixteen cysts (43%) were in the upper pole of the right kidney. Follow-up sonographic studies of 23 cysts in 22 patients for up to 5 years showed no change in size in 17 cysts (74%). The largest cyst was drained percutaneously; all other cysts were managed conservatively. No patient showed deterioration of renal function. Therefore, the authors concluded that in a pediatric patient demonstrating normal renal function, no further intervention is necessary when a simple renal cyst is identified at sonography.

T-cell lymphoma and mature nephroblastoma after synchronous bilateral Wilms' tumor.

A 15-year-old boy had lymphoblastic lymphoma of the left tonsil after being treated for bilateral Wilms' tumor (BWT) at 7 months of age. In addition, a fully differentiated Wilms' tumor was diagnosed in the remaining, partially nephrectomized left kidney. Development of second malignancies in patients with a history of BWT, as compared with those with unilateral Wilms' tumor, is discussed. A possible explanation for the concurrently diagnosed, fully differentiated Wilms' tumor in the remaining left kidney is suggested.

Effects of cisapride in patients with cystic fibrosis and distal intestinal obstruction syndrome.

In a double-blind, placebo-controlled, crossover trial, we investigated the effects of the prokinetic drug cisapride in patients with cystic fibrosis and chronic recurrent distal intestinal obstruction syndrome (DIOS). After a baseline period, 17 patients (12.9 to 34.9 years; 12 boys) received, in random order, cisapride (7.5 to 10 mg) and placebo three times daily by mouth, each for 6 months. Gastrointestinal symptoms (flatulence, abdominal pain, fullness, abdominal distension, nausea, anorexia, heartburn, diarrhea, vomiting and regurgitation) were scored three times monthly and physical examinations assessed. At baseline and at each 6-month period, assessment included food intake for 7 days, 3-day stool collection, pulmonary function tests, and abdominal radiographs. During cisapride therapy compared with placebo, there were significant reductions in flatulence (p less than 0.005), fullness, and nausea (p less than 0.05). Patients with the worst symptom scores benefited most from cisapride. With cisapride, 12 patients felt better and three worse (p less than 0.05); physicians judged 11 patients improved and two worse (p less than 0.05). No side effects were noted. There were no significant differences between cisapride and placebo periods in nutritional status, x-ray scores, pulmonary function, food intake (fat, protein, calories), stool size and consistency, and fecal losses of fat, bile acids, chymotrypsin, and calories. For acute episodes of DIOS, intestinal lavage was needed 6 times in 4 patients during treatment with cisapride, and 11 times in 6 patients receiving placebo. In comparison with unselected patients with cystic fibrosis and pancreatic insufficiency who were receiving enzyme supplements and who had no distal intestinal obstruction, fecal fat losses (percentage of intake) were almost twice as high in the study group with DIOS (31.2 +/- 20.6% vs 16.2 +/- 17.6%; p less than 0.01). We conclude that in the dosage used, long-term treatment with cisapride appears to improve chronic abdominal symptoms in patients with cystic fibrosis and DIOS, but fails to abolish the need for intestinal lavage. Cisapride treatment had no effect on digestion and nutritional status of cystic fibrosis patients with pancreatic insufficiency.

The radiologic and endoscopic investigation and etiologic classification of gastritis in children.

In 11 children the endoscopic criteria for gastritis were correlated with radiologic and pathological findings. An etiologic classification is proposed. The diagnoses included gastric involvement by Crohn's disease (five children), eosinophilic gastroenteritis (one), diffuse varioliform gastritis (two), erosive gastritis associated with Campylobacter pylori infection (two) and idiopathic erosive gastritis (one). Eight of the nine double-contrast barium studies and only one of the three single-contrast examinations correlated with the endoscopic and histologic findings. In 10 children the endoscopic results correlated well with the biopsy findings.

Malignant carcinoid within a recurrent sacrococcygeal teratoma in childhood.

Sacrococcygeal teratomas are uncommon tumors of childhood carrying a good prognosis if histologically benign and completely excised, especially if the coccyx is also excised. Carcinoids are also rare in children and only rarely associated with teratomas. We report the findings in a girl who had a malignant carcinoid within a recurrent malignant sacrococcygeal teratoma following its incomplete excision in the neonatal period. We believe that this is the first such case occurring in childhood.