Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat.

BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. METHODS: Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O(6)-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided. RESULTS: Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. CONCLUSIONS: Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

The effects of a binary mixture of benzo(a)pyrene and 7H-dibenzo(c,g)carbazole on lung tumors and K-ras oncogene mutations in strain A/J mice.

Polycyclic aromatic hydrocarbons (PAH) and N-heterocyclic aromatic hydrocarbons (NHA) are environmental pollutants formed during the incomplete combustion of organic materials. Benzo(a)pyrene (BaP) and 7H-dibenzo(c,g)carbazole (DBC) are well-characterized representatives of the PAH and NHA classes of compunds, respectively. Both are demonstrated carcinogens that frequently co-occur in environmental mixtures. This preliminary study was conducted to investigate the effects of a binary mixture of BaP and DBC on lung carcinogenicity in the strain A/J mouse as manifested by tumor development and mutations in the K-ras gene. Male A/J mice were administered the following single intraperitoneal dose (mg/kg) combinations of BaP and DBC dissolved in a 0.2-mL volume of tricaprylin--10 DBC:10 BaP; 2 DBC:10 BaP; 2 DBC:100 BaP; and 10 DBC: 100 BaP, and each of the compounds alone at the same doses. Mice were sacrificed 8 months after carcinogen treatment and lung tumor multiplicity and K-ras mutations determined (high-dose combination). The combination of DBC and BaP produced fewer tumors than the sum of all tumors produced by each compound acting alone. The frequency of tumors with K-ras mutations was also less in a sample of the 10 DBC:100 BaP treatment group than in the same-dose, single compound-treated animals. The dominant mutations produced by BaP and DBC were expressed in tumors from animals treated with the mixture.

Abdominal circumference vs. estimated weight to predict large for gestational age birth weight in diabetic pregnancy.

Early third trimester fetal abdominal circumference and sonographic fetal weight estimates were compared to predict large for gestational age birth weight in diabetic pregnancy. Both parameters have similar sensitivity, specificity, and predictive values. However, the optimal percentile cutoff values differ. Choice of birth weight standard significantly influences test characteristics. Negative prediction of large birth weight is more accurate than positive prediction. At third trimester sonography with maternal diabetes, the abdominal circumference percentile is potentially useful and should be routinely reported.

Sensitivity and specificity of ultrasound for the detection of neural tube and ventral wall defects in a high-risk population.

OBJECTIVE: To test the hypothesis that with experienced operators, sonography alone is sensitive and specific for diagnosing open neural tube and ventral wall defects in a population at risk for these disorders. METHODS: Consecutive women at risk for a fetus with an open neural tube defect because of elevated maternal serum alpha-fetoprotein (MSAFP) or family history were evaluated prospectively using prenatal sonography. Amniocentesis was not done routinely but was done for specific indications, such as limited visualization by sonography, markedly elevated MSAFP, or other risk factors for fetal chromosomal disorders. Complete postnatal outcome information was obtained, and the diagnostic accuracy of sonography was compared with that of amniocentesis plus sonography. RESULTS: Sonography alone was 97% (66 of 68) (95% confidence interval [CI] 0.898, 0.996) sensitive and 100% (n = 2189) (CI 0.998, 1.0) specific in diagnosing open neural tube defect, and was 100% sensitive (n = 17) (CI 0.805, 1.0) and specific (n = 2240) (CI 0.998, 1.0) in diagnosing ventral wall defect. In two cases of neural tube defect, there were other suspicious findings on sonography, and amniocentesis was performed for confirmation. CONCLUSION: When used by experienced operators, prenatal sonography is sensitive and specific for the diagnoses of neural tube and ventral wall defects in a targeted at-risk population.

Predictors of persistence of adnexal masses in pregnancy.

OBJECTIVE: To determine factors predicting the persistence of sonographically identified adnexal masses in pregnancy. METHODS: All patients from March 1988 to April 1993 diagnosed with an adnexal mass by obstetric sonography were reviewed. Examinations had been entered prospectively into our sonography database. Follow-up data were collected from the database, from hospital and pathology department records, and from interviews with referring obstetricians. Adnexal masses were characterized by size, sonographic appearance, and anatomic site. Persistence of the masses was determined by subsequent sonography, operative findings, or postpartum physical examinations. RESULTS: The rate of adnexal masses during pregnancy was 2.3% (432 of 18,391). Complete follow-up was available for 422 of 432. Most of the adnexal masses (76%; 320 of 422) were simple cysts with a mean diameter less than 5 cm. The remainder of the masses were simple or complex, measuring 5 cm or more in diameter. Seventy of 102 large or complex masses resolved. By multivariate analysis, the best predictors for persistence of these masses were complex appearance on sonography and size of the mass (P < .05 for both categories). CONCLUSION: Most adnexal masses identified by sonography during pregnancy were small, simple cysts that did not pose a risk to the pregnancy. Even the majority of large or sonographically complex masses resolved. The best predictors of persistence of the masses were sonographic appearance and size.

Reduction of infectious complications and costs using temporary subcutaneous implantation of PD catheters.

A limited number of authors have demonstrated that temporary subcutaneous implantation of peritoneal dialysis catheters ("Moncrief") reduces infectious complications and increases catheter life expectancy. Two operations are required to use the Moncrief catheter as compared to only one operation when peritoneal dialysis catheters are exteriorized for immediate use ("Updike"). The questions arise, then, are these findings reproducible and which catheter is the most cost-effective? In an effort to support these premises, a retrospective review of 195 patients who received peritoneal dialysis catheters from 1991 to 1995 was undertaken. Demographics, complications, life expectancy analysis, and costs were compared between Moncrief and Updike catheters. There were no significant differences between the groups, and comparisons revealed a clinically evident and statistically significant decrease in the incidence of infections with Moncrief catheters. At both one- and two-year follow-up, Moncrief catheters demonstrated a significant increase in longevity as compared to the Updike catheters. Cost comparisons between the catheter systems revealed that if patients were not undergoing immediate dialysis, placement of a Moncrief catheter was more cost-effective. Conversely, if the patient was currently undergoing dialysis, placement of an Updike catheter was more cost-effective. However, sensitivity analysis revealed that shorter exteriorization times would make the Moncrief catheter the more cost-effective choice in this patient population. In conclusion, temporary subcutaneous implantation of peritoneal dialysis catheters significantly decreases the incidence of infectious complications, increases catheter life expectancy, and is the cost-effective choice for patients who will undergo peritoneal dialysis.

Is genetic amniocentesis warranted when isolated choroid plexus cysts are found?

Our aim was to evaluate the prevalence of trisomy 18 in the setting of isolated fetal choroid plexus cysts and then to consider the risk of trisomy 18 versus the risks of genetic amniocentesis. Fetuses with choroid plexus cysts were prospectively obtained from a total mid-trimester population of 18861 fetuses with known outcomes. If the fetuses had trisomy 18, they were part of the study group and part of the control group if they had normal karyotypes. Scans were retrospectively reviewed for the characterization of cysts according to size, laterality, and appearance (simple or complex echo patterns). Chi-square analysis of contingency tables of results was performed. 208/18861 (1.1 per cent) fetuses had choroid plexus cysts. 201/208 (96.6 per cent) were normal fetuses or newborns, while 7/208 (3.4 per cent) of the fetuses with choroid plexus cysts had trisomy 18. Overall, 16 fetuses had trisomy 18 and seven (44 per cent) of these had choroid plexus cysts. 0/16 fetuses had choroid plexus cysts as the only sonographic finding. Although laterality or complexity of the cysts did not correlate with the presence or absence of a cytogenetic abnormality, cysts > or = 10 mm were more often associated with trisomy 18 than with a normal karyotype (P < 0.01). We conclude that the discovery of choroid plexus cysts in otherwise normal fetuses in the late second trimester does not by itself justify the risks of genetic amniocentesis.

Bowel abnormalities in the fetus--correlation of prenatal ultrasonographic findings with outcome.

OBJECTIVE: Our purpose was to correlate ultrasonographic findings with postnatal outcome in cases of fetal bowel pathologic disorders detected by either prenatal evaluation or diagnosed in the neonatal period. STUDY DESIGN: A total of 16,471 consecutive fetuses were scanned in the midtrimester or later. Fetuses were included in the study group if the prenatal ultrasonographic evaluation suggested gastrointestinal pathologic features or if gastrointestinal pathologic features were identified by postnatal evaluation. Prenatal ultrasonographic findings and postnatal outcome were collected by chart review. Prenatal ultrasonographic findings were compared with outcome. Results were compared by Fisher's exact test. Sensitivity and positive predictive values were determined. RESULTS: Of the 16,471 fetuses scanned, 15,090 (91.6%) had complete postnatal follow-up. Eighty-nine fetuses had a bowel lesion suspected by prenatal ultrasonography. Twenty-two had dilated bowel distal to the duodenum, 33 had isolated hyperechoic bowel, 20 had ascites, and 14 had a cystic abdominal mass. Twenty-two fetuses (22/89 or 25%) were found at neonatal evaluation to have a gastrointestinal lesion. In those fetuses with small-bowel lesions, the sensitivity of ultrasonography was 100% and the positive predictive value was 72.7%. For large-bowel lesions the sensitivity of ultrasonography was only 7.7%, and the positive predictive value was 18%. No ultrasonographic parameter could unequivocally differentiate between the normal and abnormal outcome groups, but progressive bowel dilatation in the third trimester and hyperperistalsis with a dilated bowel loop were frequently found in the cases of small bowel obstruction. Four of the cases of dilated bowel (18.2%) were related to cystic fibrosis. CONCLUSION: Bowel abnormalities in the fetus are manifest in diverse ultrasonographic findings, making accurate prediction of lesions difficult. The sensitivity of prenatal ultrasonography to detect large-bowel lesions was poor, although it was 100% sensitive in the detection of small-bowel lesions. Cystic fibrosis should be considered in all fetuses with bowel abnormalities suspected on prenatal ultrasonography.

Glycemic control and transfer of health care among adolescents with insulin dependent diabetes mellitus.

PURPOSE: To describe glycemic control among older adolescents with insulin dependent diabetes mellitus (IDDM) as they move from pediatric to adult-focused health care. METHODS: Prospective cohort study conducted in a university medical center. Participants included 82 consecutive adolescents (50 males and 32 females) with IDDM transferred from a pediatric to an adolescent/young adult diabetes clinic. Main outcome measures were the levels of total stable glycosylated hemoglobin (HbA1) obtained at each visit for up to one year before and after the transfer. RESULTS: The average age of transfer to the young adult clinic was 17.3 +/- 0.8 years. Mean age at onset of IDDM was 9.6 +/- 4.2 years (1.2 to 17.3) with duration of 7.7 +/- 3.9 years (0.7 to 16.1). Glycemic control remained unchanged following transfer (9.9% +/- 1.8 vs 10.2% +/- 1.9; t = 1.6; p = 0.125). Following transfer, both males and females maintained similar levels of glycemic control (9.8% +/- 1.7 and 10.7% +/- 1.8 respectively); although the difference between males and females was significant (t = -2.0; p = 0.048) following transfer, there was no difference in the degree of change by gender (t = -2.0; p = 0.8). In both pediatric and young adult clinics, there was no relationship between duration of IDDM (< 5 vs > or = 5 years) and HbA1. CONCLUSIONS: Transfer to an adult-focused diabetes program appears to have no negative impact on glycemic control.

Optimal nuchal skin-fold thresholds based on gestational age for prenatal detection of Down syndrome.

OBJECTIVE: We attempted to determine optimal nuchal skin-fold thresholds throughout the second trimester of pregnancy for the detection of Down syndrome. STUDY DESIGN: Thresholds of 5, 6, and 7 mm were prospectively tested in 8138 consecutive midtrimester pregnancies. The pregnancies were divided into early (14 to 18 weeks) and late (19 to 24 weeks) second-trimester time frames. The pregnancies were also subdivided by maternal age, and the same thresholds were tested for efficacy in the women < 35 years old versus those > or = 35 years old. RESULTS: There were a total of 32 fetuses with trisomy 21 in the study population. From 14 to 18 weeks' gestation, a nuchal fold thickness of > or = 5 mm was the optimal threshold. Measurements of this magnitude were found in 2.9% of pregnancies and produced a sensitivity of 42% (11/26) for the detection of Down syndrome. When adjusted for the incidence of Down syndrome in the general population, the 5 mm threshold had a positive predictive value of 1 in 48. In the 19 to 24 week gestational time frame, > or = 6 mm appeared to be the optimal threshold, yielding a positive screen rate of 3.7% with a sensitivity of 83% (5/6). The adjusted positive predictive value was 1 in 38. The sensitivity of nuchal skin-fold thickness for Down syndrome detection was similar in women < 35 and > or = 35 years old. Positive predictive value was better in the women > or = 35 years old because of the higher prevalence of affected fetuses in this group. CONCLUSIONS: Whereas definitive diagnostic testing should still be offered to all women with risk factors for a fetus with trisomy 21, differential nuchal skin-fold thresholds based on gestational age are effective for the detection of Down syndrome in pregnancies at low risk.

Impact of resident participation in a multidisciplinary diabetes team.

OBJECTIVE: To determine the impact of participation in a multidisciplinary diabetes team on pediatric residents' perceptions of team members' roles. RESEARCH DESIGN AND METHODS: Pediatric residents were assigned to a traditional diabetes clinical rotation (n = 34) or to an ambulatory multidisciplinary diabetes team within their continuity clinic (n = 21). The residents and a small sample of practicing pediatricians (n = 46) completed a Likert-type instrument at the completion of the 18-mo study. RESULTS: Multidisciplinary diabetes team residents were significantly more positive about the roles for endocrinological evaluation in monitoring compliance, for the nurse educator/certified diabetes educator in assisting with sick-day management and school behavioral problems, and for the dietician in helping with cholesterol problems. They were significantly more like practicing pediatricians in their perceptions of pediatric roles in teaching sick-day management, implementing weight reduction, assisting with conflict resolution about diabetes, screening for microvascular complications, and developing behavioral strategies for metabolic control than residents in the traditional rotation. The groups did not differ in their beliefs about patient empowerment. CONCLUSIONS: Multidisciplinary diabetes team participation may be useful in modifying specific role perceptions of pediatric residents about diabetes care. It does not appear to alter perceptions favoring greater patient empowerment.

A training algorithm for binary feedforward neural networks.

The authors present a new training algorithm to be used on a four-layer perceptron-type feedforward neural network for the generation of binary-to-binary mappings. This algorithm is called the Boolean-like training algorithm (BLTA) and is derived from original principles of Boolean algebra followed by selected extensions. The algorithm can be implemented on analog hardware, using a four-layer binary feedforward neural network (BFNN). The BLTA does not constitute a traditional circuit building technique. Indeed, the rules which govern the BLTA allow for generalization of data in the face of incompletely specified Boolean functions. When compared with techniques which employ descent methods, training times are greatly reduced in the case of the BLTA. Also, when the BFNN is used in conjunction with A/D converters, the applicability of the present algorithm can be extended to accept real-valued inputs.

Determination of Mirex in human blood serum containing polychlorinated biphenyls by using packed column gas chromatography.

An analytical method has been developed that uses electron capture/gas-liquid chromatography to determine Mirex in serum containing polychlorinated biphenyls (PCBs) (Aroclor 1260). With this method, 0.2 ppb Mirex can be determined in 4 mL serum that also contains 10 ppb PCBs. The method provides approximately 70% recovery of Mirex at 1.0 and 3.5 ppb. The coefficients of variation are 4.5 and 4.6% at 1.0 and 3.5 ppb, respectively. In a cooperative study with the Ohio Department of Health, the Centers for Disease Control used this method to determine the extent of exposure of Salem, OH, residents to Mirex. Confirmation of Mirex was obtained by using high resolution gas chromatography and high resolution mass spectrometry.

Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome.

Although congenital hydronephrosis is a common fetal disorder, ultrasonographic criteria for prenatal diagnosis remain poorly defined. In this study prenatal ultrasonographic findings were correlated with postnatal outcome in 63 fetuses with suspected hydronephrosis. Prenatal ultrasonographic measurements included length, anteroposterior diameter, and transverse diameter of the kidney and renal pelvis, as well as dorsal renal parenchymal thickness. In 45 of the 63 fetuses, hydronephrosis was confirmed postnatally. These infants were divided into two groups on the basis of renal status: (1) abnormal renal function and/or surgery required (n = 31) and (2) normal renal function with no surgery required (n = 14). The anteroposterior diameter of the renal pelvis was the simplest and most sensitive technique for prenatal diagnosis of congenital hydronephrosis, allowing identification of 100% of cases. Postnatal follow-up studies are warranted if an anteroposterior pelvic diameter is greater than or equal to 4 mm before 33 weeks or greater than or equal to 7 mm after 33 weeks.

The training and use of an artificial neural network to monitor use of medication in treatment of complex patients.

An artificial-neural-network-based drug interaction warning system was developed for use with a computerized real-time entry medical records system. The goal of the study was to provide physicians and nurses with timely warnings of potential drug interactions as therapies were prescribed. In a dialysis unit, physicians and clinical pharmacists defined rules of proper drug therapy, then trained a neural network with those rules. When the network was used to review the therapies of this patient population, a number of inconsistencies were discovered, and medication orders were changed on several patients. Real-time implementation of this monitoring system could provide messages to assure that drug therapy is consistent and proper, according to rules created by the providers of healthcare, thus preventing occasional mistakes in drug therapy.

Influence of assay method differences on multiple of the median distributions: maternal serum alpha-fetoprotein as an example.

A straightforward statistical explanation is provided to show how differences between assay methods can affect the distribution of the multiples of the median (MoM). Evaluation of the impact of assay method differences reveals that the upper tails of the MoM distribution are not affected to the same degree as the lower tails of the distribution. The disparities in MoM distributions due to assay method differences result in various sensitivity/specificity combinations for different assays having the same fixed MoM cutoffs. Disparities do not exist if risks are calculated with use of the distributions for affected and unaffected populations that are based on a center's own assay method. Applying published risk tables, however, can affect the accuracy of the risk estimates. We used maternal serum alpha-fetoprotein as an example of an assay with an established history of reporting results in MoM values; however, the concepts presented apply equally well to any assay for which results are reported in MoMs.

Sonographically measured nuchal skinfold thickness as a screening tool for Down syndrome: results of a prospective clinical trial.

Second-trimester sonographic measurement of nuchal skinfold thickness has been proposed as a potential screening tool for Down syndrome detection. The feasibility of this technique was tested in a prospective study of 3338 consecutive pregnancies at 14-21 weeks' gestation. A nuchal skinfold thickness of 6 mm or greater was identified in 47 fetuses (1.4%), 12 of whom proved subsequently by either amniocentesis or postnatal follow-up to have Down syndrome. The sensitivity of nuchal skinfold thickness for Down syndrome detection was 75% (12 of 16 cases). When adjusted for the incidence of Down syndrome in the general population (one in 710 births), the positive predictive value of nuchal skinfold thickness for Down syndrome detection was one in 13. The observed sensitivity, false-positive rate, and predictive value suggest that amniocentesis should be offered when a nuchal skinfold thickness of 6 mm or greater is observed between 14-21 weeks' gestation.

Diabetes care in schools: benefits and pitfalls of Public Law 94-142.

The implementation of the Education for All Handicapped Children Act of 1975 (Pub L No. 94-142) has brought significant changes in educational services for health-impaired children. Health-related services are one of many important services available to children under Pub L No. 94-142. For some children with IDDM, specific diabetes-related care is essential for continued progress in school. However, barriers exist that impede access to related health support services, including lack of agreement about the applicability for Pub L No. 94-142 to children with IDDM, lack of consensus as to who should provide services, and concern about liability of school personnel. This paper describes those barriers and suggests approaches to overcome them. One such approach is an Indiana State legislative amendment that provides schools with immunity from civil liability for diabetes-related care.

Fetal biometry as a screening tool for the detection of chromosomally abnormal pregnancies.

Recent studies suggest that fetal biometry may allow recognition of pregnancies at risk for Down syndrome. Second-trimester biparietal diameter (BPD)/femur length and observed-to-expected femur length ratios were examined in 48 chromosomally abnormal fetuses and compared with those of a control population composed of both low-risk patients (maternal age less than 35 years) and high-risk patients (maternal age 35 years or more). Biparietal diameter/femur length ratio correctly identified 18% of Down syndrome pregnancies with a positive predictive value of one in 169 and a false-positive rate of only 4%. When trisomies 21, 18, and 13 were considered collectively, a sensitivity of 29% and a predictive value of one in 78 were achieved, with no increase in the false-positive rate (4%). Observed-to-expected femur length ratio was less valuable in detecting chromosomally abnormal fetuses. These data suggest that the BPD/femur length ratio holds promise as a screening tool for the antenatal detection of fetal chromosomal abnormalities. Although encouraging, extrapolation of these results to other centers is not recommended without independent verification.