Effect of dioxins in mother's milk on sister chromatid exchange frequency in infant lymphocytes.

Sister chromatid exchange (SCE) frequency which was an index to the synthetic and sharp genetic toxicity was examined using the infant lymphocyte cells around postnatal of 1 year. SCE frequency as the control culture which was treated with the solvent, DMSO, alone (SCEcontrol) was 8.2 +/- 0.9/cell and as cultured with 7,8-benzoflavone (ANF) (SCEANF) was 11.8 +/- 1.4/cell. In addition, the difference of SCEANF and SCEcontrol, namely, delta SCEs became 3.6 +/- 1.3/cell. The concentration of the dioxins in the mother's milk, which had taken by the infants, in the 2-4 month postpartum was 0.95 +/- 0.51 pg-TEQ/g in the male infants, and 0.97 +/- 0.48 pg-TEQ/g in the female ones. The sex difference could not be recognized in contamination levels of the dioxins in mother's milk. The SCE frequency of the infant lymphocytes was examined in order to evaluate the genetic toxicity of the dioxins which had contaminated mother's milk. As the result, either the SCE frequencies or delta SCEs did not show any significant correlation to the dioxins. Therefore, the dioxins were considered not to induce the genetic toxicity such as the SCEs at the present levels of pollution in Japanese mother's milk around postnatal of 1 year.

The antioxidant effect of DL-alpha-lipoic acid on copper-induced acute hepatitis in Long-Evans Cinnamon (LEC) rats.

The Long-Evans Cinnamon (LEC) rats, due to a genetic defect, accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease and spontaneously develop acute hepatitis with severe jaundice. In this study we examined the protective effect of DL-alpha-Lipoic acid (LA) against acute hepatitis in LEC rats. LA was administered to LEC rats by gavage in doses of 10, 30 and 100 mg/kg five times per week, starting at 8-weeks-old and continuing till 12-weeks-old. Although LA had little effect against the increases in serum transaminase activities, it suppressed the loss of body weight and prevented severe jaundice in a dose-dependent manner. Antioxidant system analyses in liver showed that LA treatment significantly suppressed the inactivations of catalase and glutathione peroxidase, and the induction of heme oxygenase-1, an enzyme which is inducible under oxidative stress. Furthermore, LA showed dose-dependent suppressive effect against increase in nonheme iron contents of both cytosolic and crude mitochondrial fractions in a dose-dependent manner. Although at the highest dose, LA slightly suppressed the accumulation of Cu in crude mitochondrial fraction, it had no effect on the accumulation of Cu in cytosolic fraction. While LA completely suppressed the increase in lipid peroxidation (LPO) in the microsomal fraction at the highest dose, the suppressive effect against LPO in crude mitochondrial fractions was slight. From these results, it is concluded that LA has antioxidant effects at the molecular level against the development of Cu-induced hepatitis in LEC rats. Moreover, mitochondrial oxidative damage might be involved in the development of acute hepatitis in LEC rats.

Long-term prospective study on the natural history of Wolff-Parkinson-White syndrome detected during a heart screening program at school.

UNLABELLED: In the period 1985 to 1993, a total of 802 school-aged children (284 first-graders and 518 seventh-graders) were referred to our hospital for further evaluation of electrocardiographic abnormalities. Among them, 57 (male 24 and female 33) children were confirmed as having Wolff-Parkinson-White (WPW) syndrome based on the findings of 12-lead surface electrocardiograms (ECG). According to Lindsay's criteria, the locations of the accessory pathways were as follows: Left-lateral in 10 (18%), left-posterior in 2 (4%), right-free-wall in 28 (49%), anterior-septum in 13 (23%) and posterior-septum in 3 (5%). One 12-y-old girl had multiple accessory pathways. Six patients had associated diseases: Ebstein's anomaly in 4, epilepsy in 1 and mental retardation with scoliosis in 1. Follow-up periods ranged from 2.0 to 13.0 y (mean +/- SD: 8.0 +/- 3.3 y) for 23 first-graders with WPW syndrome, and from 2.0 to 13.0y (mean +/- SD: 7.3 +/- 4.2y) for 34 seventh-graders, respectively. Initially, 5 children had at least one episode of supraventricular tachycardia (SVT) by history and 6 children developed SVT during the follow-up. One girl with multiple accessory pathways and recurrent SVT required long-term drug therapy. CONCLUSIONS: The outcome of children with WPW syndrome detected by a heart screening program at school was favorable. Our 8 y follow-up of 57 children with WPW syndrome will serve as additional information concerning the indication of radio-frequency catheter ablation therapy for WPW syndrome in children.

Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice.

Recent investigations suggest that cytotoxic cytokines such as tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta or free radicals play an essential role in destruction of pancreatic beta cells in Type 1 diabetes and that, therefore, anti-oxidant or anti-TNF alpha and IL-1beta therapy could prevent the development of Type I diabetes. Troglitazone belongs to a novel class of antidiabetic agent possessing the ability to enhance insulin action provably through activating PPAR gamma and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the development of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)-injected mice. In addition, effects of troglitazone on cytokine-induced pancreatic beta cell damage were examined in vitro. Type 1 diabetes was induced by MLDSTZ injection to DBA/2 mice (40 mg/kg/day for 5 days). Troglitazone was administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from the start of or immediately after STZ injection. MLDSTZ injection elevated plasma glucose to 615 +/- 8 mg/dl 4 weeks after final STZ injection and was accompanied by infiltration of leukocytes to pancreatic islets (insulitis). Troglitazone treatment with MLDSTZ injection prevented hyperglycemia (230 +/- 30 mg/dl) and, suppressed insulitis and TNF alpha production from intraperitoneal exudate cells. TNF alpha (10 pg/ml) and IL-1beta (1 pg/ml) addition to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0.03 to approximately 3 microM) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that troglitazone prevents the development of Type 1 diabetes in the MLDSTZ model by suppressing insulitis associated with decreasing TNF alpha production from intraperitoneal exudate cells and the subsequent TNF alpha and IL-1beta-induced beta cell damage.

Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts:Mini rat, a transgenic rat carrying antisense RNA transgene for rat growth hormone.

We investigated the characteristics of hepatic cytochrome P450s and flavin-containing monooxygenase 1 (FMO1) in male Nts:Mini rats, a Wistar/Jcl-derived transgenic rat strain showing less plasma GH concentration than the parental strain. The total hepatic P450 contents of Mini rats were significantly reduced. A suppression was observed in the activities and protein expression of male-specific P450s (CYP3A and CYP2C11) and was speculated to be a potential cause of the reduction in total P450 contents. The activity and protein expression of CYP2B1 were suppressed and those of CYP2E1 and CYP2B2 were enhanced. With the exception of our data on CYP2B1, these results largely agreed with previous reports concerning GH-depletion rat models (hypophysectomized rats, rats neonatally treated with glutamate, and dwarf rats), implying that the changes in Mini rats were caused by GH insufficiency. The liver FMO1 protein expression in Mini rats was higher than that in Wistar rats but the activity was comparable, suggesting that GH is not a positive regulator of FMO expression. With their insufficient but not depleted levels of plasma GH, Mini rats may thus become another candidate for use in the investigation of GH regulation of hepatic mixed-function monooxygenases.

High-intensity basal ganglia lesions on T1-weighted images in two toddlers with elevated blood manganese with portosystemic shunts.

We report two toddlers with portosystemic shunts who had symmetrical high-signal globus pallidus lesions on T1- but not T2-weighted MRI, and measurement of whole blood manganese at 2 years of age. These cases suggest that portosystemic shunts can cause elevation of blood manganese and result in manganese accumulation in the globus pallidus, causing high signal on T1-weighted images even in asymptomatic toddlers.

Postnatal exposure to chlorinated dioxins and related chemicals on lymphocyte subsets in Japanese breast-fed infants.

Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on lymphocyte subpopulations were investigated in the peripheral blood of 36 breast-fed Japanese babies. As a result, estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) equivalents from the breast milk positively and negatively correlated with the respective percentages of CD4+ and CD8+ lymphocytes in the blood of breast-fed babies. Consequently, the ratios of CD4+ to CD8+ T cells showed significant increasing tendency with the estimated total TEQ intakes. Therefore, our study suggests that exposure to background levels of the highly toxic organochlorine compounds through the breast milk influences the human neonatal immune system.

Postnatal exposure to chlorinated dioxins and related chemicals on thyroid hormone status in Japanese breast-fed infants.

Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on thyroid hormone status were studied in the peripheral blood of 36 breast-fed Japanese infants. Estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) from the breast milk significantly and negatively correlated with the levels of triiodothyronine (T3) and thyroxine (T4) in the blood of breast-fed babies. Therefore, exposure to background levels of the highly toxic organochlorine chemicals through the breast milk may cause some effects on thyroid hormone status in Japanese infants.

Perinatal management of congenital complete atrioventricular block: report of nine cases.

BACKGROUND: The addition of fetal ultrasonography has allowed the prenatal diagnosis and observation of congenital complete atrioventricular block (CCAVB). Thus, the management of the affected fetuses should be modified accordingly. METHODS: The medical records were reviewed to identify patients with CCAVB, and clinical and laboratory data were collected. RESULTS: Nine patients with CCAVB, diagnosed prenatally, were identified. The gestational age at the time of diagnosis ranged from 18 to 38 weeks (median, 25 weeks). The gestational age and birthweight ranged from 29 to 41 weeks and from 1420 to 4075 g, respectively. An accompanying congenital cardiac anomaly was noted in three cases, including one with polysplenia syndrome. The heart rate at birth ranged from 30 to 80 bpm. In three neonates, isoproterenol was given for bradycardia. One fetus with hydrops fetalis associated with complex heart disease was treated with maternally administered digoxin, with resolution of the fluid accumulation. A permanent pacemaker was implanted in six cases: two within 1 day of birth; two during the neonatal period; one at 51 days; and the other at 2 years and 11 months of age. There were no deaths or major complications and all have remained well beyond their infancy. CONCLUSIONS: With the improvement of diagnostic methodology, more cases with CCAVB, including those with complex heart disease, could be diagnosed during fetal life. Their outcome has been steadily improving with the advances in perinatal management, pacemakers and implant techniques, irrespective of associated structural cardiac defects.

Prevention of hypoglycaemia in a patient with type Ib glycogen storage disease by an amylase (alpha-glucosidase) inhibitor.

Patients with type Ib glycogen storage disease (GSD Ib) are susceptible to hypoglycaemic episodes. To determine whether an amylase (alpha-glucosidase) inhibitor, voglibose, can be useful in the control of hypoglycaemia, we tried it in a 14-y-old male with GSD Ib. Oral administration of voglibose prolonged the duration of normoglycaemia and reduced the incidence of hypoglycaemia attacks. These findings indicate that voglibose may be useful for preventing hypoglycaemia in GSD Ib patients.

Diagnosis and management of partial anomalous pulmonary venous connection. A review of 28 pediatric cases.

Medical records, angiograms and operative records of 28 patients with partial anomalous pulmonary venous connection (PAPVC) were reviewed. Twenty patients had one anomalous pulmonary vein (APV), and 8 had more than two APVs. Twenty-five patients (89%) had APVs originating from the right lung, 2 (7%) from the left lung and 1 (4%) from both lungs. In the 25 patients with APVs originating from the right lung, 9 had APVs draining into the superior vena cava (SVC), 13 into the right atrium (RA), 1 into the inferior vena cava (IVC) and 2 into both the SVC and RA. In the 2 patients with APVs originating from the left lung, 1 had APVs draining into the RA, and the other had APVs draining into the innominate vein. The patient with APVs originating from both lungs had connection to the IVC. Twenty-three patients (82%) had additional cardiovascular defects. Surgery was performed in 13 patients who had pulmonary/systemic flow ratios greater than 2.0. The patients have done well after surgery. In 7 patients, we were unable to accurately determine the number or sites of drainage of APVs prior to surgery. We conclude that selective pulmonary angiography is indispensable for the accurate diagnosis of PAPVC.

An asymptomatic infant with isolated 3-methylcrotonyl-coenzyme: a carboxylase deficiency detected by newborn screening for maple syrup urine disease.

UNLABELLED: We describe an asymptomatic male infant with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency who came to medical attention by newborn mass screening due to elevated blood leucine. The diagnosis was made by abnormal urinary organic acids at 20 days of age and was confirmed by assay of the carboxylase activities in cultured skin fibroblasts. CONCLUSION: More attention should be paid to slight elevations of leucine levels in newborn mass screening. Urinary organic acid analysis should be performed in conspicuous cases.

Life expectancy and social adaptation in individuals with Down syndrome with and without surgery for congenital heart disease.

Life expectancy and social adaptation in 373 children with Down syndrome with and without congenital heart disease (CHD) were assessed retrospectively. Survival at age 24 years was 92.2% for patients without CHD (n=200), and 74.6% for those with CHD (n=173). Survival for those who underwent operation for cardiovascular lesions (n=95) was 87.8%, and for those not operated on despite hemodynamically significant cardiovascular lesions (n=39), it was 41.4%. Cardiac functional capacity was better in the children without congenital heart disease and in the group operated on, where most patients also attained good social adaptation. We conclude that children with Down syndrome with congenital heart disease should undergo early cardiac evaluation and surgery if indicated.

A spontaneous testicular teratoma in an ICR mouse.

A spontaneous teratoma was detected in the left testis of a 7-wk-old male ICR (Crj:CD-1) mouse. The tumor was composed of a variety of well-differentiated tissue elements from all 3 germ layers including neuronal tissue and stratified epithelium as ectoderm-derived tissues, bone, cartilage, striated muscle, and adipose tissue as mesodermal tissues, and respiratory columnar epithelium as endoderm-originated tissue. No tumor metastasis was detected. It may be of congenital origin as in strain 129 mice. To the best of our knowledge, this is the first report concerning spontaneous testicular teratoma in a strain ICR mouse.

Anthracycline-induced cardiotoxicity in children with malignancies.

The anthracyclines (ATC) have been used in the treatment of many pediatric patients with malignancies. Their use, however, has been limited by a serious and potentially irreversible cardiotoxicity. The medical records of pediatric patients with malignancies who received ATC at the Department of Pediatrics, Kyushu University, from January 1985 to December 1994 were reviewed. Among the 120 children with malignancies who received ATC, six patients (5%) developed congestive heart failure, 33 (28%) had subclinical cardiac dysfunction, whereas 81 (66%) showed no evidence of cardiac dysfunction. The incidence of ATC cardiotoxicity increased at higher cumulative doses. The earliest cardiotoxicity, however, was observed in a patient who received 180 mg/m2 unassociated with other risk factors, showing the marked individual variations in its development. Children younger than 4 years had a higher incidence of cardiotoxicity compared with those older than 4 years (P < 0.01) and are therefore more vulnerable to ATC cardiotoxicity. Because serial myocardial biopsies and stress testing are not practical in younger children, and radionuclide angiogram is rather costly and not appropriate for frequent evaluation, non-invasive tests such as echocardiography and electrocardiography (ECG) still play the main role for serial cardiac monitoring in these age groups. Radionuclide angiogram should be added as the confirmatory test modality.

Blood pressure measurement in preschool children: the Hisayama Study.

OBJECTIVE: To establish the blood pressure (BP) measurement protocol for Japanese preschool children, systolic BP (K1) and diastolic BP (K4, K5) were measured along with anthropometric values. METHODOLOGY: Commercially available mercury sphygmomanometers were used. In the first group of children (group A), BP was measured in 79 boys and 85 girls using a cuff 9 cm wide and 23 cm long. In the second group (group B), the length and circumference of the upper right arm of 147 boys and 139 girls were measured to select cuffs appropriate for their sizes. Blood pressure measurements were performed twice on the right arm of the children in the seated position at a mean interval of 5 min. RESULTS: There were no significant differences in the anthropometric values (height, bodyweight, body mass index [BMI], length and circumference of the upper arm) between groups A and B. The BP values at K1, K4 and K5 in the first measurement of group B were 91 +/- 9, 54 +/- 8, and 48 +/- 10 mmHg (boys) and 90 +/- 9, 54 +/- 8, and 48 +/- 12 mmHg (girls), respectively. There were no significant differences between the first and second measurements in both groups, however, there were significant differences in the first and second measurements of K4 between groups A and B. Multiple regression analysis by the stepwise method revealed a strong correlation between K1 and the length of the upper arm in the boys and the bodyweight in the girls: between K4 and the bodyweight in the boys and the BMI in the girls, and between K5 and the height in the boys and the upper arm circumference in the girls. CONCLUSIONS: From these results it would appear that a single measurement is sufficient under appropriate measurement conditions such as rest before measurement and the choice of the cuff size according to the upper arm circumference, and that BP is closely correlated with the anthropometric values in preschool children.

Congestive heart failure during early infancy in patients with ventricular septal defect relative to early closure.

The hemodynamic features of 44 patients requiring surgical closure of a ventricular septal defect (VSD) during early infancy were evaluated. The VSD was closed within the first 6 months of life in 29 patients (group A) and during the second 6 months in 15 patients (group B). The left-to-right (L-R) shunts were significantly greater in group A than in group B, although in all patients they were more than 50%. In contrast, the left ventricular end-diastolic volume was significantly greater in group B than in group A, whereas the right ventricular end-diastolic volume was greater in group A; the difference was not statistically significant. The step-up in blood oxygen saturation in the lower right atrium, which was significantly more in group A, indicated the L-R shunt across the patent foramen ovale (PFO). The L-R shunt across the VSD during diastole was also detected in all patients angiographically. With early infantile VSD, the larger the L-R shunt the greater was the likelihood of early surgery. Right ventricular volume overload caused by the L-R shunt across a PFO as well as through the VSD during diastole is a useful indicator of a large shunt in infants with VSD.

The mechanism of comparable serum cholesterol lowering effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, between once- and twice-daily treatment regimens in beagle dogs and rabbits.

In dogs, no significant difference in the reduction of serum cholesterol was observed among three dosing regimens of pravastatin: once in the morning (3 mg/kg), once in the evening (3 mg/kg), and twice-daily (1.5 mg/kg x 2) for 21 days. In rabbits, pravastatin was administered at a dose of 50 mg/kg once-daily given in the evening or 25 mg/kg twice-daily for 14 days; the respective serum and liver cholesterol levels were decreased by 41% and 7% in the once-daily dosing and by 51% and 11% in the twice-daily dosing. The amount of low density lipoprotein (LDL) receptor protein was increased 1.2-1.3-fold (P < 0.05) by both treatments, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the extent of up-regulated LDL receptor protein between once-daily dosing in the evening and once-daily dosing in the morning. In the experiments with rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the removal of pravastatin. These results suggest that the comparable efficacy of pravastatin between once- and twice-daily treatment could be explained by retention of up-regulated LDL receptor activity for more than 24 hr in vitro and in vivo.

Long-term outcome of coronary abnormalities in patients after Kawasaki disease.

From January 1973 through December 1992, a total of 302 patients (183 males, 119 females) with Kawasaki disease (KD) underwent coronary angiography. The age at onset of KD ranged from 2 months to 12.3 years (median 1.4 years). The age at the first angiographic evaluation ranged from 6 months to 17 years (median 3.5 years). Most of the patients (85%) had suffered from KD before 1985 and thus were treated without benefit of gamma-globulin. Follow-up varied from 6 months to 25.8 years (median 13.6 years). Coronary abnormalities were confirmed in 71 (23.5%) of 302 patients; the left coronary artery (LCA) alone was involved in 36 cases, the right coronary artery (RCA) alone in 10 cases, and both arteries in 25 cases. Serial angiographic evaluation of the 42 cases revealed different attitudes in the progress of coronary abnormalities. All large aneurysms showed a tendency to regress, although some progressed to stenotic lesions. Moderate aneurysms stayed unchanged, regressed, or progressed to stenosis or obstruction. Small aneurysm never became stenotic and frequently regressed to normal internal diameter. Aneurysms of the RCA tended to regress relatively early during the follow-up period, whereas those of the LCA gradually progressed to stenotic lesions. In 7 of 35 patients with RCA lesions, aneurysms progressed to complete obstruction and subsequent recanalization within 0.5 to 7.7 years (median 3.6 years) after the onset of KD. Most of the patients with coronary artery sequelae after KD remain asymptomatic. Serial angiographic observation is indicated for those patients who develop large coronary aneurysms during the acute phase of KD. The standard 12-lead electrocardiogram, chest roentgenogram, and exercise stress test are less sensitive for detecting and evaluating patients with coronary sequelae. For the screening of myocardial ischemia after KD, stress thallium 201 scintigraphy with dipyridamole infusion is recommended.