Increased excretion of a lipid peroxidation biomarker in autism.

It is thought that autism could result from an interaction between genetic and environmental factors with oxidative stress as a potential mechanism linking the two. One genetic factor may be altered oxidative-reductive capacity. This study tested the hypothesis that children with autism have increased oxidative stress. We evaluated children with autism for the presence of two oxidative stress biomarkers. Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha) were determined in 33 children with autism and 29 healthy controls. 8-iso-PGF2alpha levels were significantly higher in children with autism. The isoprostane levels in autistic subjects were variable with a bimodal distribution. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. There was a trend of an increase in 8-OHdG levels in children with autism but it did not reach statistical significance. There was no significant correlation between the levels of the biomarkers and vitamin intake, dietary supplements, medicine, medical disorders, or history of regression. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children.

Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans.

Large-scale poisoning occurred in central Taiwan in 1979 from ingestion of cooking oil contaminated by polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans. To determine whether in-utero exposure to these chemicals alters reproductive function, all prenatally exposed boys and appropriate controls were contacted for medical examination in 1998. Sperm of exposed children have increased abnormal morphology, reduced motility, and reduced capacity to penetrate hamster oocytes. Whether this will cause reduced fecundity, and how these effects can be extrapolated to the general population exposed to background levels of PCBs and dioxin-like chemicals, warrants further investigation.

Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese.

Despite a wide interindividual variation of cytochrome P-450 1A2 (CYP1A2) activity, genetic polymorphism of CYP1A2 has not been reported. By amplification of exons of CYP1A2 by polymerase chain reaction in eight Chinese subjects, the polymerase chain reaction products were directly sequenced. One subject showed heterozygous C2866-->G (Phe21-->Leu) polymorphism. DNA from 157 Chinese subjects (104 polychlorinated biphenyl-exposed subjects and 53 control subjects) was screened for polymorphism by single-strand conformation polymorphism method and MboII endonuclease digestion. Only 1 of 157 samples showed another heterozygous C2866-->G mutation. The subject was previously exposed to polychlorinated biphenyl and showed a value of 3.5% in the caffeine breath test. The value is not significantly higher than the mean value of polychlorinated biphenyl-exposed subjects (3.12 +/- 0.29%, mean +/- S.E.M.). The incidence of the point mutation in these Chinese subjects is less than 1%. The prevalence of the F21L mutation in other ethnic groups and its effect on the metabolic activity of CYP1A2 remain to be further evaluated.

Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer.

BACKGROUND: Herbal mixtures are popular alternatives to demonstrated therapies. PC-SPES, a commercially available combination of eight herbs, is used as a nonestrogenic treatment for cancer of the prostate. Since other herbal medicines have estrogenic effects in vitro, we tested the estrogenic activity of PC-SPES in yeast and mice and in men with prostate cancer. METHODS: We measured the estrogenic activity of PC-SPES with transcriptional-activation assays in yeast and a biologic assay in mice. We assessed the clinical activity of PC-SPES in eight patients with hormone-sensitive prostate cancer by measuring serum prostate-specific antigen and testosterone concentrations during and after treatment. RESULTS: In complementary yeast assays, a 1:200 dilution of an ethanol extract of PC-SPES had estrogenic activity similar to that of 1 nM estradiol, and in ovariectomized CD-1 mice, the herbal mixture increased uterine weights substantially. In six of six men with prostate cancer, PC-SPES decreased serum testosterone concentrations (P<0.05), and in eight of eight patients it decreased serum concentrations of prostate-specific antigen. All eight patients had breast tenderness and loss of libido, and one had venous thrombosis. High-performance liquid chromatography, gas chromatography, and mass spectrometry showed that PC-SPES contains estrogenic organic compounds that are distinct from diethylstilbestrol, estrone, and estradiol. CONCLUSIONS: PC-SPES has potent estrogenic activity. The use of this unregulated mixture of herbs may confound the results of standard or experimental therapies and may produce clinically significant adverse effects.

Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function.

Xenobiotic-induced liver injury is a clinically important etiology of hepatic disease that, if not recognized, can lead to hepatic failure. In this article we discuss the mechanisms of xenobiotic-induced liver injury, various factors that can alter the risk and severity of injury, the clinical and laboratory manifestations of injury, and the methods used to detect the presence of injury and (or) functioning liver mass.

Cecal perforation associated with sodium polystyrene sulfonate-sorbitol enemas in a 650 gram infant with hyperkalemia.

We report a 650 g, 24 week hyperkalemic newborn who developed both cecal impaction and perforation after treatment with sodium polystyrene sulfonate enemas. Flat plate abdominal radiographs revealed impacted resin as a radiodense material outlining the bowel. Pathological examination showed sodium polystyrene sulfonate crystals contained in the cecal abscess. Review of the literature in both adults and children leads us to conclude that the use of this sodium-potassium exchange resin for the treatment of hyperkalemia in this gestational age group is probably not helpful for decreasing serum potassium and may be detrimental to the infant.

Growth abnormalities in the population exposed in utero and early postnatally to polychlorinated biphenyls and dibenzofurans.

This article reviews the findings in children exposed to various levels of polychlorinated biphenyls (PCBs) and related compounds in utero and early postnatally. Yu-Cheng ("oil-disease") mothers were Taiwanese women exposed to PCBs and their heat-degradation products from the ingestion of contaminated rice oil in 1979. Children of these mothers were born growth retarded, with dysmorphic physical findings, and delayed cognitive development compared with unexposed children. In this article, findings in Yu-Cheng children born between 1978 and 1985 are summarized and compared with two other well-documented cohorts of children prenatally exposed to different levels of PCBs. Results of the investigation in Yu-Cheng children will provide important information about the toxicities, health effects, and mechanisms of PCB/PCDF exposure and demonstrate that the developing human is more sensitive than the adult to the toxic effects of these chemicals.

Intact survival of a 280-g infant: an extreme case of growth retardation with normal cognitive development at two years of age.

The care of infants born weighing less then 500 g is not only controversial but is also associated with medical uncertainties. We report the management of a growth retarded infant who weighed 280 g at birth after 26.9 weeks' gestation. The child not only survived but appears developmentally normal at two years of age. Although the infant is the smallest survivor reported, the case demonstrates the importance of gestational assessment in deciding delivery room management.

Newborn chemical exposure from over-the-counter skin care products.

Human exposure to potentially toxic environmental chemicals is a major concern to our society. Over-the-counter (OTC) skin care products are a potential source of environmental chemical exposure to newborns. A prospective study was undertaken to define existing newborn bathing practices and quantitate environmental chemical exposure from OTC skin care products. One hundred-ninety six mothers of infants discharged from our newborn nursery were asked to respond to a questionnaire concerning newborn bathing practices and OTC skin care product usage. Complete questionnaires were returned by 23% of the mothers. The average newborn had 8 +/- 3 (+/- SEM) skin care products applied with the resultant exposure to 48 +/- 18 different environmental chemicals. Forty-seven percent of our respondents used a baby powder. The average one month old was bathed 4 times a week and was shampooed 3 times weekly. Seventy-eight percent of the respondents reported that their newborn had a rash but only 45% of those reporting a rash sought professional medical advice. Thirty-seven percent of the mothers reporting a rash made a change in bathing practice or product selection. In view of our findings, the human newborn is exposed to a large number of environmental chemicals thorough topical OTC preparations. The efficacy, transcutaneous absorption and potential toxicity of these products should be investigated.

The caffeine breath test and caffeine urinary metabolite ratios in the Michigan cohort exposed to polybrominated biphenyls: a preliminary study.

A field biochemical epidemiology study was conducted using the Michigan cohort consisting of 51 rural residents exposed to polybrominated biphenyls (PBB). The study had three major objectives: a) to determine the serum half-life of the major PBB congener, hexabromobiphenyl (HBB), in the human, b) to determine if the PBB-exposed subjects had elevated cytochrome P-450I function as determined by the caffeine breath test (CBT) and the caffeine urinary metabolite ratio (CMR), and c) to determine the applicability of the CBT and CMR in field studies. PBB serum levels were detected in 36 of the 51 PBB-exposed subjects. The serum half-life of HBB was determined by comparing the current serum HBB values to the subject's previous serum values obtained 5 to 8 years earlier. The median HBB half-life was 12 years (range 4-97 years). The CBT and CMR were elevated in the subjects exposed to PBBs as compared to the values obtained from urban nonsmokers and were similar to those found in adults who smoke. A gender effect was seen in the PBB-exposed subjects, the median CBT and CMR values of the females being lower than the values of males. There was a correlation between the CBT and the HBB serum values (r2 = 0.2, p = 0.01) but not between CMR and HBB serum values. The CBT and CMR were easily conducted in the field and appear to be useful metabolic probes of cytochrome P-450I activity in human environmental toxicology.

Direct hyperbilirubinemia associated with chloral hydrate administration in the newborn.

To test the hypothesis that chloral hydrate can cause direct hyperbilirubinemia (DHB) in the newborn, two retrospective analyses of the medical records of patients admitted to a neonatal intensive care unit during an 18-month period were conducted. In one analysis of 14 newborns who had nonhemolytic DHB, 10 did not have an identified cause of DHB, and all 10 had received chloral hydrate. In the second retrospective study, all newborns who received chloral hydrate were divided into groups according to whether or not DHB had developed. The newborns with DHB, compared with those without DHB, had received a higher total accumulative dose of chloral hydrate (1035 +/- 286 vs 183 +/- 33 mg/kg [+/- 1 SEM], respectively). In the patients with DHB, the direct serum bilirubin levels increased 6.8 +/- 0.8 days after the chloral hydrate administration began and resolved after the chloral hydrate was discontinued or markedly decreased. These data support the hypothesis that prolonged use of chloral hydrate in newborns can be associated with DHB.

Urokinase therapy for a central venous catheter thrombus.

A 670 g premature infant is described in whom an intracardiac thrombus was documented. This thrombus formation probably resulted as a complication of an indwelling right atrial catheter. Thrombolytic therapy with urokinase was instituted, resulting in total and rapid dissolution. No hemorrhagic complications resulted. We believe that this particular thrombolytic therapy is safe and effective and should be considered when facing this particular complication.

Effect of growth hormone therapy in growth hormone-deficient children on cytochrome P-450-dependent 3-N-demethylation of caffeine as measured by the caffeine 13CO2 breath test.

In 6 growth hormone-deficient children, we have demonstrated that 3-N-demethylation of caffeine as measured by the 13CO2 caffeine breath test is decreased following 1 month of growth hormone therapy (8.4 +/- 1.0 vs. 6.8 +/- 1.2% 13C/2 h after treatment). These findings could be of clinical importance. The initiation of growth hormone therapy in growth hormone-deficient children could alter the clearance of drugs metabolized through the mixed-function oxidase pathway given for concurrent conditions, and necessitate adjustment of the therapeutic regimen.

Effects of pregnancy on the cytochrome P-450 system in mice.

The effects of pregnancy on the hepatic cytochrome P-450-dependent mixed-function monooxygenase system (P-450) from day 6 to day 18 of gestation were examined in the C57BL/6J mouse. Pregnancy induced an initial increase and then a decrease in total P-450 content, a decrease in microsomal aminopyrine-N-demethylase activity, and had no effect on microsomal ethylmorphine-N-demethylase activity. Pregnancy also induced in the C57BL/6J and the DBA/2J mice a new major isozyme of P-450 (P-450gest) as determined by high performance liquid chromatography and gel electrophoresis.

Dynamic trend monitoring of cerebral blood flow velocity in newborn infants.

A method for obtaining reproducible Doppler cerebral blood flow velocity (CBFV) measurements over several hours, utilizing a probe fixation technique and an on-line system for making beat-to-beat area under the curve (AUC) measurements, is described. Thirty heartbeat samples were collected at three time intervals over 3 hours in a group of 22 healthy preterm infants. The stability of the AUC measurements despite changes in behavioral state was demonstrated by randomized block ANOVA. The sampling error was +/- 6.92%, with 95% confidence intervals of +/- 13.1%. By facilitating reproducible serial measurements of CBFV, this trend monitoring technique encourages a dynamic view of cerebrovascular control, and may be used to probe central nervous system autoregulatory pathophysiology and to evaluate the effects of therapeutic interventions.