Human placental transport of cimetidine.

This study addresses the mechanism of transport of the H2-receptor antagonist, cimetidine, by the human placenta. A 4-h recycling perfusion of a single placental cotyledon of normal, term, human placenta was used. At a maternal concentration of 1 microgram/ml, cimetidine clearance from the maternal circulation was 0.58 +/- 0.16 ml/min per g placenta, a rate about one third that of antipyrine. There was no evidence of cimetidine metabolism by the placenta. Transfer of cimetidine from maternal to fetal compartments showed no saturation kinetics and was not inhibited by putative carrier competitors. Cimetidine did not accumulate against a drug concentration gradient. Fetal clearance of cimetidine was similar to maternal clearance. Studies with placental apical vesicles confirmed lack of saturability of cimetidine transport and of its concentration within vesicles. Thus, (a) cimetidine is transported across the human placenta bidirectionally at a rate about one third that of antipyrine, (b) the drug is not metabolized by the placenta, and (c) the transport is a passive one.

A marrow harvest procedure under local anesthesia.

This report details a bone marrow harvest procedure performed outside the hospital setting under local anesthesia, thereby avoiding many of the risks associated with the traditional surgical procedure. In approximately 30 minutes, 450 milliliters of marrow can be collected from eight bone punctures, containing a median of 4.18 x 10(9) cells and 33 x 10(6) progenitor cells as defined by CD34 expression. Reinfusion of a median 1.2 x 10(6) CD34+ cells/kg in 10 breast cancer and lung cancer patients after dose-intensive chemotherapy resulted in the recovery of granulocytes > 100/mm3 by day 14 and platelets > 20,000 by day 21. Without progenitor cell support, such recoveries could take 30 and 40 days, respectively. Collection of marrow using this protocol does not compromise the engraftment capability of the progenitor cells, seldom necessitates blood product support, is safer for the patient, and reduces the cost of harvesting by 75% compared to inpatient or day surgery procedures.

Glycine uptake by microvillous and basal plasma membrane vesicles from term human placentae.

Like most amino acids, glycine is present in higher concentrations in the fetus than in the mother. Unlike most amino acids, animal studies suggest fetal concentrations of glycine are minimally in excess of those required for protein synthesis. Abnormal glycine utilization has also been demonstrated in small-for-gestational age human fetuses. The mechanism(s) of glycine uptake in the human placenta are unknown. In other mammalian cells glycine is a substrate for the A, ASC and Gly amino acid transport systems. In this study human placental glycine uptake was characterized using microvillous and basal plasma membrane vesicles each prepared from the same placenta. In both membranes glycine uptake was mediated predominantly by the sodium-dependent A system. Competitive inhibition studies suggest that in microvillous vesicles the small percentage of sodium-dependent glycine uptake not inhibited by methylaminoisobutyric acid (MeAIB) shares a transport system with glycine methyl ester and sarcosine, substrates of the Gly system in other tissues. In addition there are mediated sodium-independent and non-selective transport mechanisms in both plasma membranes. If fetal glycine availability is primarily contingent upon the common and highly regulated A system, glycine must compete with many other substrates potentially resulting in marginal fetal reserves, abnormal utilization and impaired growth.

Sonographically detected hyperechoic fetal bowel: significance and implications for pregnancy management.

OBJECTIVE: The clinical significance of sonographically detected hyperechoic fetal bowel has not been fully established. This report describes the natural history, pregnancy outcome, and associated features of 30 cases of prenatally diagnosed hyperechoic fetal bowel. METHODS: Fetal bowel of similar or greater echogenicity than surrounding bone was considered hyperechoic. Fetuses so diagnosed were compared with matched controls and with our general obstetric population to determine the relative frequencies of cystic fibrosis, perinatal death, fetal growth retardation, and fetal trisomies. RESULTS: The incidence of hyperechoic fetal bowel during the study period was 0.2% (30 of 12,776 fetuses). Four of the 30 fetuses (13.3%) with hyperechoic bowel were found to have cystic fibrosis, as compared with one in 2200 (0.05%) in the general population. Hyperechoic fetal bowel was also associated with increased risks for perinatal death (16.7%, versus 3.8% in matched controls and 1.9% in the general obstetric population) and fetal growth retardation (23.3% versus 1.9% and 5%, respectively). One fetus with hyperechoic bowel had trisomy 18, an incidence of cytogenetic abnormalities of 3.3%. This was not significantly greater than observed in our general obstetric population (1.2%) (P > .25). CONCLUSIONS: The sonographic finding of hyperechoic fetal bowel is associated with an increased risk for cystic fibrosis, perinatal death, and growth retardation. The risk of fetal trisomy in cases of isolated hyperechoic bowel appears small. When detected, hyperechoic bowel should prompt a complete and careful fetal anatomical survey, consideration of parental carrier testing for cystic fibrosis, and serial sonographic assessment of fetal growth, with cytogenetic testing reserved for cases demonstrating other structural malformations.

Fetal pyelectasis and Down syndrome: is genetic amniocentesis warranted?

An association between pyelectasis and Down syndrome has recently been reported. The purpose of this investigation was twofold: 1) to test the hypothesis that pyelectasis is more common in fetuses with Down syndrome, and 2) to determine whether genetic amniocentesis should be offered when dilated renal pelves are identified during fetal ultrasound examination. The study population of 5944 fetuses was separated into two groups by infant outcome: 1) phenotypically and/or chromosomally normal, and 2) chromosomally abnormal. Each group was examined for the presence of pyelectasis, defined as an anteroposterior renal pelvic diameter of 4 mm or greater before 33 weeks or 7 mm or greater after 33 weeks. Pyelectasis was observed in 17.4% (four of 23) of Down syndrome fetuses versus only 2% (120 of 5876) of normal controls, a statistically significant difference (P less than .001). The predictive value of pyelectasis for Down syndrome (one in 90) compares favorably with other accepted indications for genetic amniocentesis, such as advanced maternal age and low maternal serum alpha-fetoprotein (MSAFP). When fetuses with concomitant sonographic abnormalities were excluded, the predictive value of isolated pyelectasis fell to one in 340. We conclude that although renal pyelectasis is more common in Down syndrome fetuses, genetic amniocentesis should be reserved for those cases presenting other risk factors such as advanced maternal age, low MSAFP, or other sonographic abnormalities.

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.

Brain corticotropin-releasing hormone receptors on neurons and astrocytes.

UNLABELLED: Corticotropin-releasing hormone (CRH) exerts many potent effects within brain and is considered an important brain neuroregulator. CRH acts via receptors that are widely distributed throughout brain which exhibits highest CRH receptor concentrations in extrahypothalamic regions. We have previously characterized CRH receptors in heterogeneous extrahypothalamic forebrain cell cultures consisting of neurons and glia, and have shown them to exhibit similar kinetic and pharmacological characteristics as CRH receptors in pituitary and in situ brain. However, it is not known whether CRH receptors are present on neurons, glia or both. We tested the hypothesis that CRH receptors are present on neurons in extrahypothalamic forebrain cell cultures derived from day 17-18 fetal rats by characterizing receptors in predominantly neuronal (N), glial/astrocytic (G) cultures and mixed (M) cultures. Mean CRH receptor concentrations (fmol/mg protein) in N (10.4), G (9.4), and M (9.8) cultures were similar. Following Scatchard analyses derived from competition curves, all cell populations exhibited similar mean high-affinity/low-capacity (Kd = 1.0-1.9 nM; Bmax = 183-388 fmol/mg protein) and low-affinity/high-capacity (Kd = 92-104 nM; Bmax = 2034-5008 fmol/mg protein) classes of binding sites. IN CONCLUSION: (1) Neurons and astrocytes in fetal extrahypothalamic brain cell cultures contain CRH receptors which exhibit similar concentrations and similar kinetic characteristics. (2) These observations suggest that biological effects of CRH in brain could be mediated via actions on neurons and/or glial astrocytes.

Teratology: principles and practice.

Gross anomalies of structure and/or function affect 2 to 4 per cent of all human newborns and are the leading cause of perinatal mortality in this country. Despite their significance, the etiology of most such defects remains unclear. A majority are unassociated with any identifiable cause; a small but significant percentage are attributed to heritable disorders of either a Mendelian (single gene) or chromosomal nature. Drugs and environmental exposures are currently implicated in only a small percentage of affected pregnancies. Nevertheless, an awareness of the principles of teratogenesis, an appreciation for the role--though imprecise--of placental transfer and fetal drug disposition, and avoidance of known teratogens currently offers our best hope for the study and prevention of birth defects.

Placental amino acid uptake in normal and complicated pregnancies.

Amino acids are the essential substrates for fetal growth and catabolism. The fetus is dependent on the placenta for the provision of amino acids, the first step being concentration of amino acids within the syncytiotrophoblast for subsequent transfer to the fetus. A reliable technique for the isolation of human syncytiotrophoblast plasma membrane has been described, and the suitability of this preparation for the study of amino acid uptake and membrane transport has been well documented. Using this technique, the microvillous vesicle uptake of alpha-aminoisobutyric acid (AIB), a nonmetabolizable amino acid, has been determined over multiple time points for normal (NL) pregnancies and those complicated by pregnancy-induced hypertension (PIH), non-insulin-dependent diabetes mellitus (NIDDM) and those delivering small-for-gestational-age (SGA) neonates. There was no significant difference in AIB uptake between NL pregnancies and those complicated by PIH or NIDDM. Compared to each of the above, AIB uptake by the SGA group was significantly less at each time point. These results suggest that normal placental amino acid transport mechanisms may be altered in SGA pregnancies. If so, such alterations may interfere with the normal provision of nutrients to the fetus and ultimately contribute to impaired growth in utero.

A comparative evaluation of the transport of H2-receptor antagonists by the human and baboon placenta.

Using a single cotyledon perfusion model, the placental transport of four H2-receptor antagonists, cimetidine, famotidine, nizatidine, and ranitidine, was determined and compared using normal term human and normal preterm baboon placentas. In both the human and baboon placentas, the transport of each agent was similar whether administered singly or in combination with the other drugs. Drug transport was the same in both directions, maternal-to-fetal and vice versa, indicating a lack of preferential transfer. The H2-receptor antagonists were transported at about 40% the rate of the freely diffusable reference compound, antipyrine. There were no significant differences between the human and baboon in any of the parameters of placental function evaluated. Placental glucose and oxygen consumptions, and lactate production were comparable in the human and baboon preparations. The transport and clearance of each of the H2-antagonists were similar in each species.

The fetus with gastroschisis managed by a trial of labor: antepartum and intrapartum complications.

OBJECTIVE: To assess the rate of antepartum and intrapartum complications of fetuses with antenatally diagnosed gastroschisis managed in a center that advocates a trial of labor. STUDY DESIGN: A retrospective review. The medical records of 49 fetuses (1988 to 1997) who were prenatally diagnosed with gastroschisis by a sonologist in the Ultrasound Genetic Unit, Department of Obstetrics and Gynecology at Washington University, were reviewed. RESULTS: Oligohydramnios and intrauterine growth restriction were diagnosed in 23% and 49% of the pregnancies, respectively. A total of 22 women underwent induction of labor nine for nonreassuring fetal testing, four for premature rupture of membranes, five for marked bowel dilatation, one for preeclampsia, and three for other reasons. Cesarean section (CS) was performed in 16 of 43 (37%) of women. The indications for CS were fetal distress (9 of 16 women), chorioamnionitis (2 of 16 women), breech presentation (3 of 16 women), and physician discretion (2 of 16 women). No significant differences in Apgar scores were observed between the fetuses. Fetuses who were delivered by CS for fetal distress were more likely to have undergone an induction of labor (91% versus 44%), and they were smaller than fetuses with no evidence of fetal distress (2220 +/- 105 gm versus 2613 +/- 80 gm, p < 0.05). CONCLUSION: The incidence of antepartum and intrapartum complications in fetuses with gastroschisis is high. The rate of CS can reach 37%. These data may aid clinicians in counseling patients with gastroschisis.

Small bowel obstruction secondary to a prior Moschcowitz procedure.

The Moschcowitz procedure has been advocated for the correction of large enteroceles. Documented complications of this technique are rare. Following is a review of this procedure with the presentation of a unique delayed complication.

Sonographic recognition of major malformations and aberrant fetal growth in trisomic fetuses.

Structural malformations and growth retardation are commonly observed in chromosomally abnormal newborns. This study assesses the sensitivity of ultrasound for detecting aberrant fetal growth patterns and chromosome-related major malformations. The study population consisted of 74 trisomic fetuses (trisomy 13, 9; trisomy 18, 22; trisomy 21, 43). Overall, 63% (38 of 60) of trisomic fetuses had at least one major malformation on postnatal examination. One or more major anomalies were identified by prenatal sonography in 68% (26 of 38) of these malformed fetuses and 43% (26 of 60) of the entire trisomic population. Midtrimester onset growth retardation was evident in 43% of fetuses with trisomy 13 and 59% of fetuses with trisomy 18. These findings suggest that a systematic fetal anatomic survey can be a powerful screening tool for the prenatal detection of chromosome abnormalities.

The effects of cocaine on neutral amino acid uptake by human placental basal membrane vesicles.

OBJECTIVE: Prior studies have demonstrated that cocaine binds to human placental microvillous membrane vesicles at a single high-affinity site and that both 10 and 500 nmol/L cocaine inhibit sodium-dependent alanine uptake. The purpose of this study was to characterize cocaine binding to human placental basal plasma membrane and to determine the effects of cocaine on basal vesicle uptake of alanine and leucine. STUDY DESIGN: Basal vesicles were isolated from the placentas of uncomplicated human pregnancies with no history of cocaine use. The binding of tritiated cocaine to basal vesicle membrane and the uptakes of tritiated cocaine, alanine, and leucine were determined with filtration assays. Alanine and leucine uptakes were measured in the presence and absence of sodium and 10 and 500 nmol/L cocaine. Cocaine binding was characterized with Scatchard analyses, and uptakes were compared by means of Student t tests. RESULTS: Tritiated cocaine bound to basal membrane at two separate high-affinity sites. Sodium-dependent alanine uptake was significantly inhibited only by 500 nmol/L cocaine. Sodium-independent amino acid uptake was unaffected by cocaine. CONCLUSION: Cocaine may interfere with fetal growth by impairing the activity of sodium-dependent amino acid transporters in both the microvillous and basal membrane. These membranes may be differentially sensitive to the effects of cocaine on such transporters.

Cocaine inhibits alanine uptake by human placental microvillous membrane vesicles.

OBJECTIVE: The aim of this study was to determine the effects of cocaine on alanine uptake by human placental microvillous membrane vesicles and to characterize cocaine binding to the microvillous membrane. STUDY DESIGN: Microvillous vesicles were isolated from the placentas of 10 human pregnancies with no history of cocaine use. The binding of tritiated cocaine to microvillous vesicle membrane and uptake of tritiated cocaine and tritiated alanine were determined with the use of filtration assays. Scatchard analyses were used to characterize cocaine binding. Sodium-independent and sodium-dependent uptake of tritiated alanine was measured in the presence and absence of (-)cocaine and its stereoisomer (+)cocaine. Uptakes were compared with the use of Student t tests. RESULTS: Specific tritiated cocaine binding accounted for approximately 96% of total binding at a single-component high-affinity site in the microvillous membrane. The mediated sodium-dependent component of alanine uptake was significantly (p < 0.01) reduced in the presence of (-)cocaine but was unaffected by (+)cocaine. CONCLUSION: Cocaine may contribute to fetal growth restriction by interfering with the normal activity of placental amino acid transporters necessary to maintain the nutrient gradients associated with normal fetal growth.

Ellipsomicroscopy for surface imaging: contrast mechanism, enhancement, and application to CO oxidation on Pt(110).

Ellipsomicroscopy for surface imaging (EMSI) is a powerful new tool for studying spatiotemporal adsorbate pattern formation on catalyst surfaces. It is a surface-sensitive technique that is able to measure submonolayer coverage of adsorbates. The imaging of the sample's surface achieves a spatial sensitivity, making it possible to measure nonuniformity of adsorbate coverage. The image contrast, however, depends strongly on the setup of the instrument. The optimum setup can be calculated from the ellipsometric properties of the catalyst/adsorbate system and the intrinsic parameters of the EMSI instrument. Optimizing the setup of the EMSI instrument permitted enhancement of the image contrast over the previous setup. As a result, new features in CO oxidation on Pt(110) were discovered.

Effect of ethanol on human placental transport of model amino acids and glucose.

Prior studies in rodents, sheep, and subhuman primates have shown that ethanol, especially after chronic exposure, inhibits the transport of amino acids by the placenta. A small decrease in glucose transport by rat placenta chronically exposed to ethanol has also been noted. With human placental slices, however, only pharmacological (high) concentrations of ethanol impaired uptake of amino acids, and there are no data on glucose transport. In the present study, the effect of brief exposure to ethanol on human placental transport of model amino acids and glucose was studied by two techniques not previously jointly employed for this--the perfused human placental cotyledon and human placental vesicle systems. The nonmetabolizable amino acids, alpha-aminoisobutyric (AIB) acid and cycloleucine (CLEU), as well as D-glucose, and nonmetabolized glucose (3-O-methyl-D-glucose), were used as probes. AIB and CLEU are transferred normally by active transport and D-glucose by facilitated transport from maternal to fetal compartments. The perfused placental system was exposed to ethanol (300-500 mg%) for 2-4 hr and the vesicles to 200-400 mg% ethanol for times varying from 10 min to 48 hr. There was no impairment of AIB, D-glucose, or 3-O-methyl-D-glucose transfer by ethanol using these techniques. Normally, about 60% of AIB transport by human placenta is sodium dependent. This component (using the vesicle system) was also not impaired by ethanol. Ethanol caused a very small decrease of CLEU clearance by the perfused human placenta (p = 0.05) but not using vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life of young adults with idiopathic short stature: effect of growth hormone treatment. Dutch Growth Hormone Working Group.

The aim of the study was to evaluate whether treatment with recombinant human growth hormone (rhGH) affects the quality of life of young adults who were diagnosed as idiopathic short stature (ISS) during childhood, and whether their quality of life and aspects of the personality are different from normal. Experiences and expectations concerning rhGH treatment of the subjects and their parents were also investigated. Eighty-nine subjects were included into the study: 24 subjects (16M, 8F) were treated with rhGH from childhood, whereas 65 subjects (40M, 25F) were never treated. At the time of the interview all subjects had attained final height [mean (SD) -2.3 (0.9) SDS for Dutch references], and the age of the treated subjects was 20.5 (1.0) y, and 25.7 (3.5) y of the control subjects (p < 0.001). The level of education was similar, but the treated subjects had less often a partner compared to the control subjects (adjusted for age and gender, p < 0.001). The Nottingham Health Profile and Short Form 36 Health Survey showed no difference in general health state between treated and control subjects, and the healthy Dutch age-specific references (norm group). Although 74% of the subjects reported one or more negative events related to their height, and 61% would like to be taller, only 22% and 11% were willing to trade-off at Time Trade-Off and Standard Gamble, respectively. The personality of the subjects, which was measured by the Minnesota Multiphasic Personality Inventory, was not different from the norm group. The satisfaction with the rhGH treatment was high, as it had caused 12 (8) cm and 13 (7) cm gain in final height according to the subjects and parents, respectively. Based on initial predicted adult height (Bayley & Pinneau), this gain was only 3.3 (5.6) cm. We concluded that although the treated subjects had a partner less often when compared to the control subjects, the quality of life of subjects with ISS at adult age is normal and appears not to be affected by rhGH therapy, The treated subjects were very satisfied with the treatment, probably by overestimation of the final height gain.