Lawrence D. Devoe

Perinatal outcome and amniotic fluid index in the antepartum and intrapartum periods: A meta-analysis

OBJECTIVE Our purpose was to perform a meta-analysis of studies on the risks of cesarean delivery for fetal distress, 5-minute Apgar score <7, and umbilical arterial pH <7.00 in patients with antepartum or intrapartum amniotic fluid index >5.0 or <5.0 cm. STUDY DESIGN Using a MEDLINE search, we reviewed all studies published between 1987 and 1997 that correlated antepartum or intrapartum amniotic fluid index with adverse peripartum outcomes. The inclusion criteria were studies in English that associated at least one of the selected adverse outcomes with an amniotic fluid index of </=5.0 cm versus >5.0 cm. Contingency tables were constructed for each study, and relative risks and standard errors of their logs were calculated. Fixed-effects pooled relative risks were calculated for groups of studies that were homogeneous, whereas random-effects pooled relative risks were calculated for significantly heterogeneous groups of studies. RESULTS Eighteen reports describing 10,551 patients met our inclusion criteria. An antepartum amniotic fluid index of </=5.0 cm, in comparison with >5.0 cm, is associated with an increased risk of cesarean delivery for fetal distress (pooled relative risk, 2.2; 95% confidence interval, 1.5-3.4) and an Apgar score of <7 at 5 minutes (pooled relative risk, 5.2; 95% confidence interval, 2.4-11.3). An intrapartum amniotic fluid index of </=5.0 cm is also associated with an increased risk of cesarean delivery for fetal distress (pooled relative risk, 1.7; 95% confidence interval, 1.1-2.6) and an Apgar score <7 at 5 minutes (pooled relative risk, 1.8; 95% confidence interval, 1.2-2.7). A poor correlation between the amniotic fluid index and neonatal acidosis was noted in the only study that examined this end point. More than 23,000 patients are necessary to demonstrate that the incidence of umbilical arterial pH <7.00 is 1.5 times higher among those with oligohydramnios in labor than among those with adequate amniotic fluid index (alpha = 0.05; beta = 0.2) CONCLUSIONS An antepartum or intrapartum amniotic fluid index of </=5.0 cm is associated with a significantly increased risk of cesarean delivery for fetal distress and a low Apgar score at 5 minutes. There are few reports linking amniotic fluid index and neonatal acidosis, the only objective assessment of fetal well-being. A multicenter study with sufficient power should be undertaken to demonstrate that a low amniotic fluid index is associated with an umbilical arterial pH <7.00.

Cloning of the Human Thiamine Transporter, a Member of the Folate Transporter Family

We have isolated a cDNA from human placenta, which, when expressed heterologously in mammalian cells, mediates the transport of the water-soluble vitamin thiamine. The cDNA codes for a protein of 497 amino acids containing 12 putative transmembrane domains. Northern blot analysis indicates that this transporter is widely expressed in human tissues. When expressed in HeLa cells, the cDNA induces the transport of thiamine (Kt = 2.5 ± 0.6 μm) in a Na+-independent manner. The cDNA-mediated transport of thiamine is stimulated by an outwardly directed H+ gradient. Substrate specificity assays indicate that the transporter is specific to thiamine. Even though thiamine is an organic cation, the cDNA-induced thiamine transport is not inhibited by other organic cations. Similarly, thiamine is not a substrate for the known members of mammalian organic cation transporter family. The thiamine transporter gene, located on human chromosome 1q24, consists of 6 exons and is most likely the gene defective in the metabolic disorder, thiamine-responsive megaloblastic anemia. At the level of amino acid sequence, the thiamine transporter is most closely related to the reduced-folate transporter and thus represents the second member of the folate transporter family.

Human Na(+)-dependent vitamin C transporter 1 (hSVCT1): primary structure, functional characteristics and evidence for a non-functional splice variant.

We report here on the cloning and functional characterization of human Na(+)-dependent vitamin C transporter 1 (SVCT1). The human SVCT1 cDNA, obtained from a Caco2 cell cDNA library, encodes a protein of 598 amino acids with 12 putative transmembrane domains. The SVCT1-specific transcript, 2.4 kb in size, is expressed in kidney, liver, small intestine, thymus and prostate. When expressed heterologously in HRPE cells, SVCT1 mediates the transport of ascorbate, the reduced form of vitamin C, in a Na(+)-dependent manner. The transporter is specific for ascorbate with a K(t) of approximately 75 microM. The relationship between the cDNA-specific uptake rate of ascorbate and Na(+) concentration is sigmoidal with a Na(+):ascorbate stoichiometry of 2:1, indicating that the transport process is electrogenic. In Caco2 cells and in normal human intestine, SVCT1 also exists as a non-functional splice variant with a four amino acid sequence inserted between E-155 and V-156. The splice variant results from the use of a donor site 12 bp downstream of the normal donor site.

Serial noninvasive evaluation of cardiovascular hemodynamics during pregnancy

M-mode echocardiography, in combination with electrocardiography and phonocardiography, has been used to measure pulmonary capillary pressure as well as other cardiac functions. Serial hemodynamic evaluations by use of this technique were performed in seven healthy pregnant women in the recumbent position. Each patient had five studies: four antenatal studies and one postpartum study that served as a control. Mean pulmonary capillary pressure was within normal limits throughout pregnancy and the puerperium. Cardiac output did not increase significantly by the end of the first or second trimester but became elevated by 31% in the early third trimester. This elevation in cardiac output persisted until delivery and resulted from a comparable increase in heart rate. Stroke volume and ejection fraction did not change significantly, while peripheral vascular resistance fell, although not significantly, reaching a nadir at approximately 28 weeks of gestation. Our findings indicate that maternal cardiac output increases due to an increased heart rate and reduced afterload.

Cloning and functional characterization of a Na+-independent, broad-specific neutral amino acid transporter from mammalian intestine

We have isolated a cDNA from a rabbit intestinal cDNA library which, when co-expressed with the heavy chain of the human 4F2 antigen (4F2hc) in mammalian cells, induces system L-like amino acid transport activity. This protein, called LAT2, consists of 535 amino acids and is distinct from LAT1 which also interacts with 4F2hc to induce system L-like amino acid transport activity. LAT2 does not interact with rBAT, a protein with a significant structural similarity to 4F2hc. The 4F2hc/LAT2-mediated transport process differs from the 4F2hc/LAT1-mediated transport in substrate specificity, substrate affinity, tissue distribution, interaction with D-amino acids, and pH-dependence. The 4F2hc/LAT2-associated transport process has a broad specificity towards neutral amino acids with K(t) values in the range of 100-1000 microM, does not interact with D-amino acids to any significant extent, and is stimulated by acidic pH. In contrast, the 4F2hc/LAT1-associated transport process has a narrower specificity towards neutral amino acids, but with comparatively higher affinity (K(t) values in the range of 10-20 microM), interacts with some D-amino acids with high affinity, and is not influenced by pH. LAT2 is expressed primarily in the small intestine and kidney, whereas LAT1 exhibits a much broader tissue distribution.

Cloning and Expression of a b0,+-like Amino Acid Transporter Functioning as a Heterodimer with 4F2hc Instead of rBAT A NEW CANDIDATE GENE FOR CYSTINURIA

We have cloned a transporter protein from rabbit small intestine, which, when coexpressed with the 4F2 heavy chain (4F2hc) in mammalian cells, induces a b0,+-like amino acid transport activity. This protein (4F2-lc6 for the sixth member of the 4F2 light chain family) consists of 487 amino acids and has 12 putative transmembrane domains. At the level of amino acid sequence, 4F2-lc6 shows significant homology (44% identity) to the other five known members of the 4F2 light chain family, namely LAT1 (4F2-lc1), y+LAT1 (4F2-lc2), y+LAT2 (4F2-lc3), xCT (4F2-lc4), and LAT2 (4F2-lc5). The 4F2hc/4F2-lc6 complex-mediated transport process is Na+-independent and exhibits high affinity for neutral and cationic amino acids and cystine. These characteristics are similar to those of the b0,+-like amino acid transport activity previously shown to be associated with rBAT (protein related to b0,+ amino acid transport system). However, the newly cloned 4F2-lc6 does not interact with rBAT. This is the first report of the existence of a b0,+-like amino acid transport process that is independent of rBAT. 4F2-lc6 is expressed predominantly in the small intestine and kidney. Based on the characteristics of the transport process mediated by the 4F2hc/4F2-lc6 complex and the expression pattern of 4F2-lc6 in mammalian tissues, we suggest that 4F2-lc6 is a new candidate gene for cystinuria.

The nonstress test as a diagnostic test: A critical reappraisal

In the past decade the nonstress test has become a major method of assessing high-risk pregnancy. Although many studies have been published, there has been a lack of rigorous adherence to the standard criteria for diagnostic testing, that is, presentation of test specificity, sensitivity, predictive value, and the prevalence of abnormal outcomes in the populations studied. Furthermore, the populations studied vary widely in composition, testing conditions, methods of test interpretation, and clinical management. The authors undertake a review of these studies, with a focus on these issues, in an attempt to indicate potential problems involved in current test usage and to suggest avenues for needed clinical investigation.

Nonimmune hydrops fetalis: Clinical experience and factors related to a poor outcome

Twenty-one cases of nonimmune hydrops fetalis diagnosed at the Medical College of Georgia during a 2-year period are presented. All fetuses satisfied strict diagnostic criteria and were evaluated according to a standard protocol. The corrected mortality rate was 95% with pulmonary hypoplasia being the most common cause of perinatal death. The mean gestational age at diagnosis was 24.8 weeks; in 57% of the cases the cause of nonimmune hydrops fetalis was identified. Fifteen fetuses had serial ultrasound assessment and in 19 cases postnatal evaluation was performed. Two factors that consistently conveyed a poor perinatal outcome were ultrasonographic evidence of malformation and/or the presence of persistent pleural effusions. A method for the quantification of fetal pleural effusions is presented and its clinical relevance is discussed.

Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta

OBJECTIVE We sought to investigate the expression of cannabinoid receptors in human placenta and BeWo choriocarcinoma cells and study their role in the regulation of the serotonin transporter. STUDY DESIGN Expression of the 2 types of cannabinoid receptors (CB1 and CB2) in human placenta and BeWo cells was investigated by reverse transcriptase-polymerase chain reaction and Northern blot analysis. The involvement of the receptors in the regulation of the serotonin transporter expression was studied by using a cannabinoid receptor agonist (WIN 55212-2). BeWo cells were treated with the agonist in the presence or absence of forskolin, and the serotonin transporter activity was measured by assessing paroxetine-sensitive serotonin transport. Serotonin transporter density in cell membranes was monitored by measuring paroxetine-sensitive binding of RTI-55, a specific high-affinity ligand for the transporter. Agonist-induced changes in intracellular levels of cyclic adenosine monophosphate were also monitored. RESULTS Reverse transcriptase-polymerase chain reaction and Northern blot analysis demonstrated unequivocally that human placenta and BeWo cells express both types of cannabinoid receptors. Treatment of BeWo cells with the receptor agonist blocked the activity of the constitutive, as well as the forskolin-induced, serotonin transporter without affecting the serotonin transporter density. This effect is not mediated by alterations in intracellular cyclic adenosine monophosphate levels. CONCLUSION The results show that cannabinoid receptors are expressed in human placenta and BeWo cells and play a role in the regulation of the serotonin transporter activity. Human placenta is therefore a direct target for cannabinoids, and marijuana use during pregnancy is likely to affect the placental clearance of serotonin through the serotonin transporter.

Pleural effusions and pulmonary hypoplasia

Nine cases of fetuses with pleural effusions are presented in which the diagnosis was made by ultrasound before the thirtieth week of gestation. A ratio of lung span to hemithorax diameter was calculated and ranged from 0.44 to 0.77 (mean 0.60). At autopsy, pulmonary hypoplasia was confirmed in all cases by criteria based on the ratio of lung weight to total body weight. Because pleural effusions occurring in the midtrimester can be detected and may lead to pulmonary hypoplasia, consideration should be given to definitive in utero therapy when no other major fetal abnormality is detected.