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Biomedical subjects

D K Manchester

Publications and source records attributed to D K Manchester.

At least 37 records · Page 2Linked to original sources
PubMed1988

Dosimeters of human exposure to carcinogens: polycyclic aromatic hydrocarbon-macromolecular adducts.

The metabolic activation of polycyclic aromatic hydrocarbons (PAH), for example benzo[a]pyrene, leads to the formation of carcinogen-macromolecular adducts. Methods that make it possible to detect low levels of these adducts in human peripheral blood samples should be useful in the dosimetry of human exposure to carcinogens. We demonstrated previously the usefulness of enzyme immunoassays and of synchronous fluorescence spectroscopy (SFS) for detecting and characterizing low levels of PAH-macromolecular adducts present in synthetic adduct mixtures. These methods have now been refined and applied to the analysis of samples of peripheral blood collected from occupationally exposed individuals (coke-oven workers) and from people attending smoking cessation clinics. The results of both immunoassays and SFS show the presence of benzo[a]pyrene diol epoxide (BPDE)-DNA, BPDE-haemoglobin and other putative PAH-macromolecular adducts in peripheral blood samples from certain individuals.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Ah receptor in human placenta: stabilization by molybdate and characterization of binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, and benzo(a)pyrene.

Aryl hydrocarbon hydroxylase (AHH, cytochrome P1-450) is highly inducible in several human cells and tissues exposed to specific halogenated and nonhalogenated aromatic chemicals of the "3-methylcholanthrene-type." In laboratory animals AHH induction is known to be regulated by binding of inducers to the Ah receptor, a soluble intracellular protein. However, the induction mechanism in the human species is incompletely understood largely because the Ah receptor, which seems to be essential to the induction process, has not previously been detectable in certain human cells and tissues (including placenta) that are highly responsive to AHH induction. We found that human placenta contains high concentrations of Ah receptor (comparable to the receptor concentrations in rat and mouse liver) but that special modifications were necessary in the assay techniques in order to detect and accurately quantitate receptor binding. Receptor was detected at concentrations approximately equal to 100 fmol/mg cytosol protein using [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the radioligand. This high concentration of specific binding sites was present only if the placental tissue was initially homogenized in a buffer containing sodium molybdate (10 or 20 mM). Without molybdate in the homogenizing buffer, specific [3H]TCDD binding was only about 35 fmol/mg. Specific Ah receptor binding also was detectable with [3H]-3-methylcholanthrene and, to a lesser extent, with [3H]-benzo(alpha)pyrene. The receptor sedimented near 9S on sucrose gradients whether molybdate was present or not. About 80% of specific binding was lost if excessive charcoal was used to adsorb "nonspecifically bound" ligand from cytosol prior to gradient analyses. The apparent affinity with which [3H]TCDD bound to Ah receptor in human placental cytosol was relatively low (apparent Kd approximately equal to 5 to 8 nM) when compared with the affinity of [3H]TCDD binding in rat or mouse hepatic cytosols (Kd approximately equal to 1 to 3 nM). These data suggest that while molybdate has very little effect on the quantity or molecular size of the rodent Ah receptor assay, it is very important in stabilizing the human Ah receptor. Our experiments demonstrate that human placenta contains a high concentration of Ah receptor and suggest that AHH induction in placenta is mediated through a receptor mechanism analogous to that previously established in tissues and cells from laboratory animals.

Benzo(a)pyrene↗
PubMed1987

Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature.

The Noonan syndrome (NS) is a true multiple congenital anomalies (MCA) syndrome with numerous manifestations. An association with lymphedema has been noted, but its pathogenesis is not fully understood. Nine new cases and a review of the literature explore the role of lymphedema in NS, including its pathogenesis, presentations, and phenotypic effects. Consideration is given to developmental stage at time of onset, chronicity, resolution, and anatomic site. It appears likely that lymphedema is a much more frequent concomitant in NS than previously realized. The major source of lymphedema in NS appears to be a presently undefined dysplasia of lymphatic vessels of unknown cause. Further study of lymphedema may provide an understanding of its role in shaping the NS phenotype. Comparison with other MCA syndromes and animal models is made in this regard. Relevance to prenatal diagnosis and treatment is discussed.

Adult↗
PubMed1987

High resolution proton NMR spectroscopy of human amniotic fluid.

Human amniotic fluid (HAF) is a dynamic system whose characteristics depend on continuous interchanges between fetal and maternal circulations. HAF reflects not only the environment of the fetus but may also provide information about fetal development or pathology. The concentration of HAF constituents varies with gestational age and pathological states. The number of the compounds currently implicated in fetal developmental pathology are relatively few. Currently used assay methods are not adequate to totally explain or predict the complex biochemistry of the fetus. The purpose of this work was to investigate HAF with NMR spectroscopy. In the present study HAF was obtained from 47 women undergoing routine amniocentesis. Cells were separated for karyological analysis and the supernatant was acid-extracted, lyophilized and re-suspended in D20 resulting in a concentration increase over native fluid. 1H NMR spectra were obtained at 360 MHz and 60 MHz. Eighteen compounds including several amino acids, were identified using parallel reference and standard addition protocols. NMR spectroscopy detected compounds of known clinical importance including glucose, leucine, isoleucine, lactate and creatinine. In conclusion, we have demonstrated that a number of physiologically relevant compounds are readily observable in HAF using 1H NMR spectroscopy. This technique can currently provide valuable information regarding HAF composition and has the potential of being used in vivo in the future.

Amniotic Fluid↗
PubMed1987

Severe polyhydramnios: incidence of anomalies.

The sonograms of 195 singleton pregnancies complicated by polyhydramnios were reviewed, and follow-up information was obtained on 191 patients. A grading system was developed that differentiated mild from severe polyhydramnios using real-time or static sonographic equipment. Mild polyhydramnios was present in 138 (71%), and severe polyhydramnios was present in 57 (29%). Previously it has been reported that 60% of cases of polyhydramnios are idiopathic and the pregnancies have a normal outcome. Twenty percent are associated with maternal abnormalities and 20% are associated with fetal anomalies. In this study, pregnancies with severe polyhydramnios had a much greater prevalence of fetal anomalies (75%) than pregnancies with mild polyhydramnios (29%). The 57 singleton pregnancies with severe polyhydramnios were analyzed in depth. Fourteen (25%) of the fetuses were normal; 43 (75%) had significant congenital abnormalities that predominantly involved the CNS, gastrointestinal tract, heart, and genitourinary tract. In all fetuses with primary CNS abnormalities, polyhydramnios was diagnosed at or before 30 weeks of gestation, while in most of the fetuses (83%) with gastrointestinal abnormalities it was diagnosed after 30 weeks. Sonographic findings correlated closely with the findings noted at birth or autopsy. In patients with severe polyhydramnios, normal sonograms were sensitive in excluding major congenital anomalies and, thus, were helpful in providing the parents with favorable prognoses. Sonograms should be performed in patients with polyhydramnios to identify congenital anomalies and to provide information regarding prognosis for fetal outcome.

Adult↗
PubMed1987

Tracheoesophageal fistula in utero. Twenty-two cases.

A retrospective review of 22 infants born with tracheoesophageal fistula (TEF) with in utero sonograms was performed and the literature was reviewed. TEF or esophageal atresia should be considered when there is polyhydramnios and an absent fluid-filled stomach; these findings were seen in 32% of our cases. Amniotic fluid flows freely through some TEFs, resulting in a normal amount of amniotic fluid and a fluid filled stomach (six of 22 patients), while in other cases, the fluid does not traverse the fistula easily and polyhydramnios results. Polyhydramnios was present in 62% of our cases and was the most common sonographic finding. The earliest age at which polyhydramnios was diagnosed was 24 weeks. Sonography will detect approximately one third of fetuses with TEF; an improved outcome is expected in these fetuses.

Female↗
PubMed1986

Twin study methodology and variability in xenobiotic placental metabolism.

The present study assesses the contribution of genetic and environmental factors to variability in placental aryl hydrocarbon hydroxylase and glutathione transferase activities using twin study methodology. Twin placentas were collected at the time of delivery. The placenta, except for a single layer of maternal decidua, consists of fetal tissue exhibiting fetal genotype. Microsomal and cytosolic fractions were prepared under stringent protocols to prevent enzyme activity loss. There were two monozygotic-monochorionic pairs, five monozygotic-dichorionic pairs, and 21 dizygotic-dichorionic pairs that showed measurable aryl hydrocarbon hydroxylase activity using the direct fluorometric assay. Most of the mothers were smokers. Aryl hydrocarbon hydroxylase activity was measured with two different substrates, benzo(a)pyrene and 7-ethoxyresorufin. Glutathione transferase activity was measured using glutathione and 1-chloro-2,4-dinitrobenzene as substrates for a spectrophotometric assay that follows the conversion of the aromatic substrate. Twin pair similarity was calculated with intraclass correlation coefficients. There is a high correlation between the activities of the two aryl hydrocarbon hydroxylase substrates (r = .814), but no correlation between aryl hydrocarbon hydroxylase and glutathione transferase activity levels. There is little evidence of genetic variability underlying the variation in the enzyme activities because monozygotic-dichorionic twins are no more similar to each other for the three substrate activities than are the dizygotic twins. To delineate the prenatal environmental influences on placental enzyme variability, dichorionic placentation was subdivided further into contiguous and noncontiguous placental position. Lower intraclass correlation coefficients are obtained for the dizygotic twins whose placentas were noncontiguous compared with dizygotic twins with contiguous placentas. The results suggest that most of the variability seen in these placental enzyme systems is due to environmental differences within uteri, rather than genetic variability in the population. This does not negate the possibility that between-pair, or population, variability may have a genetic component, because even dizygotic twins share a large proportion of their genes. This study points out that a significantly variable environment exists within the human uterus.

Aryl Hydrocarbon Hydroxylases↗
PubMed1986

Perinatal autopsy: its clinical value.

The clinical value of the routine autopsy was studied in 172 sequential cases of perinatal deaths. Of these cases 139 (81%) were autopsied including 52 fetal deaths and 87 neonatal deaths. The clinically assigned cause of death was compared with the cause of death as identified by the autopsy. In 26% (nine fetal and 27 neonatal deaths) the autopsy was the sole means of establishing the cause of death. A need for specific genetic counseling or evaluation was identified in 62 of the 139 perinatal deaths. In 30 (48%) cases the autopsy was the sole source of information highlighting this need. The autopsy is an important clinical tool providing useful information to the perinatal clinician. Besides providing specific causes of death, it can correct clinical impressions and identify genetic factors that require further assessment and counseling.

Autopsy↗
PubMed1985

Two massive congenital intracranial immature teratomas with neck extension.

In this report we detail two congenital intracranial immature teratomas, noteworthy for their massive intracranial growth and extension through the skull with compromise of neck structures. Cytogenetic studies were done in both cases on the fetuses and their tumors and are the first in the literature. Few previously reported congenital intracranial teratomas have been described with neck extension. In both cases, polyhydramnios was detected by prenatal ultrasonography and was possibly caused by the laryngoesophageal and/or brainstem distortion by neoplasm. Possible reasons for such excessive, unchecked growth of teratomas in the fetal period are discussed.

Adult↗
PubMed1984

Maternal smoking increases xenobiotic metabolism in placenta but not umbilical vein endothelium.

It is unclear whether placental xenobiotic metabolism can protect the human conceptus. In particular, the role of placental metabolism of toxic components of cigarette smoke such as polycyclic aromatic hydrocarbons (PAHs) is poorly understood. We hypothesized that increased aryl hydrocarbon hydroxylase (AHH) activity observed in placentas from smokers might help clear PAHs from maternal circulation and thereby prevent transplacental induction of AHH by PAHs. Our studies of AHH activity in human placentas and umbilical vein endothelium support this premise. While AHH activity was significantly increased in placentas from smokers compared with activity in placentas from nonsmokers, AHH activity in umbilical vein endothelium from these same pregnancies was unaffected by maternal smoking and remained low. In order to confirm that AHH present in endothelium was inducible, we also demonstrated dose-dependent increases in AHH activity in primary cultures of human umbilical vein endothelial cells exposed to PAHs. These findings may indicate first pass protection of the fetus by placental xenobiotic metabolism, or that endogenous factors suppress AHH induction in the fetus but not placenta.

Aryl Hydrocarbon Hydroxylases↗
PubMed1984

Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.

Cytochromes P-450 are a family of enzymes responsible for metabolism of drug and xenobiotics, such as carcinogen, and certain physiological compounds, such as steroids and prostaglandins. We prepared a monoclonal antibody (MAb 1-7-1) to a polycyclic hydrocarbon-induced rat cytochrome P-450 that antigenically defines and inhibits a type of cytochrome P-450 responsible for aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin deethylase (ECD) activity in human placenta. We examined the placentas from single and twin births from mothers who smoked cigarettes and nonsmokers. The MAb 1-7-1 inhibited the smoking-induced AHH activity of essentially the entire population of placentas by 70 to 95%. Thus, up to 95% of the AHH in a population of human placentas is catalyzed by a type of cytochrome P-450 that contains an antigenic site recognized by MAb 1-7-1. A second type of cytochrome P-450, which is insensitive to MAb 1-7-1, is responsible for the ECD activity in the placentas of nonsmokers. In the placentas from smokers, both types of P-450 contribute to ECD activity. Their ratios can be determined by the amount of inhibition by MAb 1-7-1 which ranges from 0 to 70%. The placentas from both dizygotic and dichorionic monozygotic twins show extraordinarily high intrapair concordance for both the absolute amounts of AHH and ECD and their inhibition by MAb 1-7-1 compared with unrelated individuals, indicating that interindividual differences in these parameters of biological activity are not due to random variation or experimental error. Our results show that the amount of activity of antigenically unique types of cytochrome P-450 responsible for different drug and carcinogen reactions can be measured in different individuals by the amount of their inhibition by highly specific monoclonal antibodies. These findings may have general application to studies on the relationship cytochrome P-450 phenotype to population differences in drug and carcinogen biotransformation.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

An outbreak of rotavirus-associated neonatal necrotizing enterocolitis.

An outbreak of necrotizing enterocolitis and hemorrhagic gastroenteritis occurred in two nurseries during 25 days in August 1982. Eleven of the 40 patients in these nurseries during that time developed disease (attack rate 27.5%). In seven of the 10 patients with gastrointestinal disease, stool samples tested for human rotavirus were positive by ELISA, whereas in 20 unaffected infants, no stools tested demonstrated HRV (P = 0.0001). Eleven staff members had serologic evidence of recent HRV infection. Comparison of risk factors traditionally associated with the development of NEC between the affected and unaffected infants revealed no significant differences. Rotavirus infection was the only finding that was highly correlated with this epidemic.

Cross Infection↗
PubMed1983

Fetal heart rate in relation to body mass.

In contrast to the inverse relation of heart rate to body mass in adult mammals, the heart rate of immature fetuses is unrelated to body mass and approximately constant among different species. With maturation, fetal heart rate decreases in a large mammal but tends to increase in a small mammal. These maturational changes reduce the difference between the heart rate of a term fetus and the heart rate which is "appropriate for body mass" as calculated by means of the allometric equation for adults. The comparative physiology of fetal heart rate supports the hypothesis that immature fetuses of small and large mammals have similar oxygen consumption rates per unit body mass.

Aging↗
PubMed1982

Glutathione S-transferase activities in placentas from smoking and non-smoking women.

1. Microsomal mono-oxygenase activity toward 7-ethoxyresoryfin, and cytosolic glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene were determined in 53 placentas obtained at delivery from smoking and non-smoking women. 2. Whereas mono-oxygenase activity was clearly stimulated in placentas from women who smoked, no parallel enhancement of glutathione S-transferase activity was evident. 3. This disparity in response could result in imbalance among placental detoxication systems following exposure to certain compounds.

Cytochrome P-450 CYP1A1↗