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Human placenta as a target organ for cocaine action: Interaction of cocaine with the placental serotonin transporter
316
Citations from the literature/Int. J. Gynecol. Obstet. 47 (1994) 315-323
Reducing the need for amniocentesisin women 35 years of age or older with serum markers for screening Haddow J.E.; Palomaki G.E.; Knight G.J.; Cunningham G.C.; Lustig L.S.; Boyd P.A. USA NEW ENGL J MED 1994 330/16(1114-1118) Background. As maternal age advances, the risk of fetal Down’s syndrome increases. Pregnant women 35 years of age or older are routinely offered amniocentesis because of this risk. Recently, maternal serum markers have been reported to be useful in screening for Down’s syndrome, primarily in younger women. We therefore investigated whether offering amniocentesis only to selected women 35 years of age or older who were identified by screening measurements in serum might prove a useful alternative to the current practice. Methods. We studied 5385 women with singleton pregnancies who were 35 years of age or older and were undergoing routine amniocentesis. Along with information about the pregnancy, we obtained a serum sample for measurement of a-fetoprotein, unconjugated estriol, and human chorionic gonadotropin. Individual estimates of the risk of Down’s syndrome in the fetus were calculated for each pregnancy before the karyotype was known. Results. If amniocentesis had been reserved for the women calculated to have a risk greater than I in 200 of having a fetus with Down’s syndrome, 48 of the 54 cases of Down’s syndrome (89%) would have been identified; 25% of the unaffected pregnancies would also have been identified as being at high risk for Down’s syndrome (false positives). Seven of I5 fetuses (47%) with other trisomies, I I of 25 (44%) with sex aneuploidy, and 1 of 9 (11%) with miscellaneous chromosomal abnormalities would also have been detected. In practice, such screening would have made 75% of the amniocenteses unnecessary, along with a proportion of the amniocentesis-associated fetal losses. If the cutoff for the risk of Down’s syndrome were set higher than I in 200, both the rate of detection and the false positive rate would be lower. Conversely, these rates would be higher if the cutoff were set lower. Conclusions. Prenatal screening of serum to generate individual estimates of the risk of Down’s syndrome in the fetus can provide a basis for decision making in the cases of women 35 years of age or older, as it does in younger pregnant women, and is an alternative to current testing practices.
Maternity blues and major endacrinechanges: Cardiff puerperal mood and hormonestudy II Harris B.; Lovett L.; Newcombe R.G.; Read G.F.; Walker R.; Riad-Pahmy D. GBR BR MED J 1994 30816934(949-953) Gbje,,,ives - To define relation between mood and concentratious of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. Design - Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. Setting - Antenatal clinic in university hospital, obstetric inpatient
unit, patients’ homes. Subjects - 120 of I56 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because cesarean section required. Main outcome measures - Concentrations of progesterone and cortisol in saliva samples; women’s moods assessed by various scores for depression. Results - Changes in salivary progesterone and cortisol concentrations were similar to those already characterized for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day live postpartum (P c 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P< 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P h O.Ol), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score ~8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmoliI Y32 IO pmobl, respectively, P= 0.03; ten days postpartum 88 pmol/I v 114 pmol/I, P = 0.048). Cortisol concentrations were not significantly associated with mood. Conclusion - Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.
PERINATOLOGY Humanplacenta as a target organ for cocaine action: Interaction of cocaine with the placental serotonia transporter Prasad P.D.; Leibach F.H.; Mahesh V.B.; Ganapathy V. USA PLACENTA 1994 1513(267-278) The interaction of cocaine and its analog Z&carbomethoxy3&(4-iodophenyl) tropane (RTI-55) with the human placental serotonin transporter was investigated. The function of the placental serotonin transporter was assayed using three different approaches: serotonin uptake in purified human placental brush border membrane vesicles, paroxetine binding in placental brush border membrane vesicles, and serotonin uptake in cultured human placental choriocarcinoma cells. The interaction of cocaine and RTI-55 with the transporter was studied by determining the effects of these compounds on the transporter function. Cocaine and RTI-55 were found to be potent inhibitors of the transporter in all three approaches. The inhibition was competitive in nature in all cases. The inhibition constant (K(i)) for cocaine was not influenced significantly by the duration of time allowed for the compound to interact with the transporter. In contrast, the inhibition constant for RTI-55 was influenced markedly by this parameter. The longer the time allowed for interaction of RTI-55 with the transporter, the smaller was the K(i) value. These results suggest that the association kinetics for the interaction of cocaine and RTI-55 with the placental serotonin transporter are significantly dif-
Citations from the literature / Int. J. Gynecol. Ohster. 47 (1994) 315-323
ferent. When equilibrium interaction was allowed, cocaine inhibited the function of the transporter with a K(i) of 0.09 pM. It is concluded that cocaine and its analog RTI-55 are potent inhibitors of the function of the serotonin transporter that is expressed in the normal human placenta and in cultured human placental choriocarcinoma cells. Since the reported values for cocaine concentration in the blood of cocaine users are severalfold higher than the inhibition constant for cocaine, the present study strongly suggests that the function of the placental serotonin transporter may be severely impaired by maternal use of cocaine during pregnancy. These findings may be relevant to fetal and placental complications of cocaine abuse during pregnancy.
Current topk: Confined placental mosaicism ad fetal development
intrauterine
Kalousek D.K. CAN
PLACENTA 1994 1513(219-230) Chromosomal mosaicism is the presence of two or more cell lines with different chromosomal complements in an individual derived from a single zygote (which is distinguishable from chimerism in which an individual is derived from more than one zygote). Mosaicism may involve a number of different karyotypic abnormalities including those for whole sets of chromosomes (polyploidy, including triploidy and tetraploidy), trisomies, sex chromosomal anomalies and chromosomal rearrangements. Mosaicism itself may be present in all the tissues of the body and placenta, or it may only be seen in certain tissues or may be restricted to only the placenta and extraembryonic membranes. The type of mosaicism seen depends upon the stage of development at which it originated. the tissue types to which the abnormal cell lines were distributed and the cell cycle times of both the normal and abnormal cells. The phenotypic effects or consequences of chromosomal mosaicism may be dramatic. During the pregnancy, high levels of mosaicism are seen in early abnormal preimplantation embryos, spontaneous abortions, intrauterine growth restriction and intrauterine fetal death. However, not all cases of mosaicism are serious and the presence of a normal cell line may dilute the effects of an abnormal cell line to such an extent that in many cases mosaicism will remain undetected because the consequences are not severe. Investigations of chromosomal mosaicism were, until recently, restricted to those cells which could be induced to divide and be karyotyped from metaphase analysis. Advances in molecular genetics and cytogenetics have made possible the identification of chromosomal abnormalities, specifically mosaicism in interphase cells. The identification of abnormalities such as confined placental mosaicism and its association with uniparental disomy has led to the recognition that chromosomal mosaicism plays a major role in abnormal human development and dysmorphology. An understanding of mosaicism and the role of the placenta during development, including the phenomenon of trisomic zygote rescue, is helping to cast light on problems in prenatal diagnosis, many of which involve confined placental mosaicism.
Neaaatal cerebral Duppler flow vehxity waveform term infant with cerebral pathology
317 in the pre-
Mires G.J.; Pate1 N.B.; Forsyth J.S.; Howie P.W. GBR
EARLY HUM DEV 1994 36/3 (213-222) In a longitudinal study of 217 infants delivering at < 37 completed weeks gestation, Doppler flow velocity waveforms were obtained, and resistance index (RI) values calculated from the middle (MCA) and anterior (ACA) cerebral arteries during the first IO days of life. Sixty infants demonstrated ultrasound evidence of cerebral pathology, of which five cases were congenital, and an additional I3 cases were complicated by patent ductus arteriosus during the study period. The Doppler data obtained during the first week of life from the remaining 42 infants who developed cerebral pathology, and IS infants who had evidence of metabolic acidosis at delivery without ultrasound evidence of cerebral pathology were compared with local reference data obtained from non-acidotic infants with normal cranial ultrasound from 24 h of age. In those infants who had evidence of minor periventricular hemorrhage alone (Grade l/II PVH), there was no significant difference between the ACA or MCA RI during the study period compared with the reference data. In those groups of infants who demonstrated major PVH (Grade III/IV) or persistent periventricular flares, the ACA and MCA RI was found to be consistently significantly higher than the reference group throughout the study period. In those infants who developed ultrasound evidence of periventricular cystic leukomalacia (PVCL), the MCA RI was significantly lower than the reference data between 48 and 72 h of age, there being no significant difference in the ACA RI. The Doppler tindings in those infants with evidence of metabolic acidosis at delivery (umbilical arterial pH < 7.20; BD > 8 mmol/l) but with normal ultrasound findings were similar to those infants who developed PVCL, namely a significant fall in MCA RI between 48 and 72 h of life, with no significant difference in the ACA RI during the study period. These findings suggest that variable changes in cerebral vascular resistance occur with the evolution of, or as a consequence of the development of cerebral pathology in the pre-term infant, and these changes of increased and decreased vascular resistance are discussed. Further investigation of the changes occurring in the cerebral circulation in the early neonatal period of infants who develop PVCL is required to clarify the vascular changes taking place, but if the findings of this study are confirmed, this technique may provide a means of identifying infants at risk of developing ischemic cerebral pathology at an early stage when it may be possible to initiate therapeutic intervention to limit the cerebral damage. Neonatal cerebral Doppler fluw velocity wavefoms cumplkmtal pm-term infant: Reference values
in the un-
Mires G.J.; Pate1 N.B.; Forsyth J.S.; Howie P.W. GBR
EARLY HUM DEV 1994 36/3 (205-212) In a longitudinal study of 2 I7 infants delivering at < 37 completed weeks gestation, Doppler flow velocity waveforms were obtained and resistance index (RI) values calculated from the
Citations from the literature/Int. J. Gynecol. Obstet. 47 (1994) 315-323
Reducing the need for amniocentesisin women 35 years of age or older with serum markers for screening Haddow J.E.; Palomaki G.E.; Knight G.J.; Cunningham G.C.; Lustig L.S.; Boyd P.A. USA NEW ENGL J MED 1994 330/16(1114-1118) Background. As maternal age advances, the risk of fetal Down’s syndrome increases. Pregnant women 35 years of age or older are routinely offered amniocentesis because of this risk. Recently, maternal serum markers have been reported to be useful in screening for Down’s syndrome, primarily in younger women. We therefore investigated whether offering amniocentesis only to selected women 35 years of age or older who were identified by screening measurements in serum might prove a useful alternative to the current practice. Methods. We studied 5385 women with singleton pregnancies who were 35 years of age or older and were undergoing routine amniocentesis. Along with information about the pregnancy, we obtained a serum sample for measurement of a-fetoprotein, unconjugated estriol, and human chorionic gonadotropin. Individual estimates of the risk of Down’s syndrome in the fetus were calculated for each pregnancy before the karyotype was known. Results. If amniocentesis had been reserved for the women calculated to have a risk greater than I in 200 of having a fetus with Down’s syndrome, 48 of the 54 cases of Down’s syndrome (89%) would have been identified; 25% of the unaffected pregnancies would also have been identified as being at high risk for Down’s syndrome (false positives). Seven of I5 fetuses (47%) with other trisomies, I I of 25 (44%) with sex aneuploidy, and 1 of 9 (11%) with miscellaneous chromosomal abnormalities would also have been detected. In practice, such screening would have made 75% of the amniocenteses unnecessary, along with a proportion of the amniocentesis-associated fetal losses. If the cutoff for the risk of Down’s syndrome were set higher than I in 200, both the rate of detection and the false positive rate would be lower. Conversely, these rates would be higher if the cutoff were set lower. Conclusions. Prenatal screening of serum to generate individual estimates of the risk of Down’s syndrome in the fetus can provide a basis for decision making in the cases of women 35 years of age or older, as it does in younger pregnant women, and is an alternative to current testing practices.
Maternity blues and major endacrinechanges: Cardiff puerperal mood and hormonestudy II Harris B.; Lovett L.; Newcombe R.G.; Read G.F.; Walker R.; Riad-Pahmy D. GBR BR MED J 1994 30816934(949-953) Gbje,,,ives - To define relation between mood and concentratious of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. Design - Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. Setting - Antenatal clinic in university hospital, obstetric inpatient
unit, patients’ homes. Subjects - 120 of I56 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because cesarean section required. Main outcome measures - Concentrations of progesterone and cortisol in saliva samples; women’s moods assessed by various scores for depression. Results - Changes in salivary progesterone and cortisol concentrations were similar to those already characterized for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day live postpartum (P c 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P< 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P h O.Ol), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score ~8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmoliI Y32 IO pmobl, respectively, P= 0.03; ten days postpartum 88 pmol/I v 114 pmol/I, P = 0.048). Cortisol concentrations were not significantly associated with mood. Conclusion - Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.
PERINATOLOGY Humanplacenta as a target organ for cocaine action: Interaction of cocaine with the placental serotonia transporter Prasad P.D.; Leibach F.H.; Mahesh V.B.; Ganapathy V. USA PLACENTA 1994 1513(267-278) The interaction of cocaine and its analog Z&carbomethoxy3&(4-iodophenyl) tropane (RTI-55) with the human placental serotonin transporter was investigated. The function of the placental serotonin transporter was assayed using three different approaches: serotonin uptake in purified human placental brush border membrane vesicles, paroxetine binding in placental brush border membrane vesicles, and serotonin uptake in cultured human placental choriocarcinoma cells. The interaction of cocaine and RTI-55 with the transporter was studied by determining the effects of these compounds on the transporter function. Cocaine and RTI-55 were found to be potent inhibitors of the transporter in all three approaches. The inhibition was competitive in nature in all cases. The inhibition constant (K(i)) for cocaine was not influenced significantly by the duration of time allowed for the compound to interact with the transporter. In contrast, the inhibition constant for RTI-55 was influenced markedly by this parameter. The longer the time allowed for interaction of RTI-55 with the transporter, the smaller was the K(i) value. These results suggest that the association kinetics for the interaction of cocaine and RTI-55 with the placental serotonin transporter are significantly dif-
Citations from the literature / Int. J. Gynecol. Ohster. 47 (1994) 315-323
ferent. When equilibrium interaction was allowed, cocaine inhibited the function of the transporter with a K(i) of 0.09 pM. It is concluded that cocaine and its analog RTI-55 are potent inhibitors of the function of the serotonin transporter that is expressed in the normal human placenta and in cultured human placental choriocarcinoma cells. Since the reported values for cocaine concentration in the blood of cocaine users are severalfold higher than the inhibition constant for cocaine, the present study strongly suggests that the function of the placental serotonin transporter may be severely impaired by maternal use of cocaine during pregnancy. These findings may be relevant to fetal and placental complications of cocaine abuse during pregnancy.
Current topk: Confined placental mosaicism ad fetal development
intrauterine
Kalousek D.K. CAN
PLACENTA 1994 1513(219-230) Chromosomal mosaicism is the presence of two or more cell lines with different chromosomal complements in an individual derived from a single zygote (which is distinguishable from chimerism in which an individual is derived from more than one zygote). Mosaicism may involve a number of different karyotypic abnormalities including those for whole sets of chromosomes (polyploidy, including triploidy and tetraploidy), trisomies, sex chromosomal anomalies and chromosomal rearrangements. Mosaicism itself may be present in all the tissues of the body and placenta, or it may only be seen in certain tissues or may be restricted to only the placenta and extraembryonic membranes. The type of mosaicism seen depends upon the stage of development at which it originated. the tissue types to which the abnormal cell lines were distributed and the cell cycle times of both the normal and abnormal cells. The phenotypic effects or consequences of chromosomal mosaicism may be dramatic. During the pregnancy, high levels of mosaicism are seen in early abnormal preimplantation embryos, spontaneous abortions, intrauterine growth restriction and intrauterine fetal death. However, not all cases of mosaicism are serious and the presence of a normal cell line may dilute the effects of an abnormal cell line to such an extent that in many cases mosaicism will remain undetected because the consequences are not severe. Investigations of chromosomal mosaicism were, until recently, restricted to those cells which could be induced to divide and be karyotyped from metaphase analysis. Advances in molecular genetics and cytogenetics have made possible the identification of chromosomal abnormalities, specifically mosaicism in interphase cells. The identification of abnormalities such as confined placental mosaicism and its association with uniparental disomy has led to the recognition that chromosomal mosaicism plays a major role in abnormal human development and dysmorphology. An understanding of mosaicism and the role of the placenta during development, including the phenomenon of trisomic zygote rescue, is helping to cast light on problems in prenatal diagnosis, many of which involve confined placental mosaicism.
Neaaatal cerebral Duppler flow vehxity waveform term infant with cerebral pathology
317 in the pre-
Mires G.J.; Pate1 N.B.; Forsyth J.S.; Howie P.W. GBR
EARLY HUM DEV 1994 36/3 (213-222) In a longitudinal study of 217 infants delivering at < 37 completed weeks gestation, Doppler flow velocity waveforms were obtained, and resistance index (RI) values calculated from the middle (MCA) and anterior (ACA) cerebral arteries during the first IO days of life. Sixty infants demonstrated ultrasound evidence of cerebral pathology, of which five cases were congenital, and an additional I3 cases were complicated by patent ductus arteriosus during the study period. The Doppler data obtained during the first week of life from the remaining 42 infants who developed cerebral pathology, and IS infants who had evidence of metabolic acidosis at delivery without ultrasound evidence of cerebral pathology were compared with local reference data obtained from non-acidotic infants with normal cranial ultrasound from 24 h of age. In those infants who had evidence of minor periventricular hemorrhage alone (Grade l/II PVH), there was no significant difference between the ACA or MCA RI during the study period compared with the reference data. In those groups of infants who demonstrated major PVH (Grade III/IV) or persistent periventricular flares, the ACA and MCA RI was found to be consistently significantly higher than the reference group throughout the study period. In those infants who developed ultrasound evidence of periventricular cystic leukomalacia (PVCL), the MCA RI was significantly lower than the reference data between 48 and 72 h of age, there being no significant difference in the ACA RI. The Doppler tindings in those infants with evidence of metabolic acidosis at delivery (umbilical arterial pH < 7.20; BD > 8 mmol/l) but with normal ultrasound findings were similar to those infants who developed PVCL, namely a significant fall in MCA RI between 48 and 72 h of life, with no significant difference in the ACA RI during the study period. These findings suggest that variable changes in cerebral vascular resistance occur with the evolution of, or as a consequence of the development of cerebral pathology in the pre-term infant, and these changes of increased and decreased vascular resistance are discussed. Further investigation of the changes occurring in the cerebral circulation in the early neonatal period of infants who develop PVCL is required to clarify the vascular changes taking place, but if the findings of this study are confirmed, this technique may provide a means of identifying infants at risk of developing ischemic cerebral pathology at an early stage when it may be possible to initiate therapeutic intervention to limit the cerebral damage. Neonatal cerebral Doppler fluw velocity wavefoms cumplkmtal pm-term infant: Reference values
in the un-
Mires G.J.; Pate1 N.B.; Forsyth J.S.; Howie P.W. GBR
EARLY HUM DEV 1994 36/3 (205-212) In a longitudinal study of 2 I7 infants delivering at < 37 completed weeks gestation, Doppler flow velocity waveforms were obtained and resistance index (RI) values calculated from the