[Show abstract][Hide abstract] ABSTRACT: In the post-Genome era, new concepts emerge about the growth regulation of uterine leiomyomata. Screening of leiomyoma and myometrial tissues with DNA arrays revealed numerous genes up-regulated in leiomyomata that were not known to be expressed in the human uterus. GluR2, a subunit of a ligand-gated cation channel, is up-regulated in leiomyomata relative to myometrium by 15- to 30-fold at the protein and mRNA level and is localized in endothelial cells. GluR2 pre-mRNA in leiomyoma and myometrial tissues is nearly 100% edited at the Q/R site, indicative of low Ca(2+) permeability of the ion channels. In spontaneous leiomyomata in women or leiomyomata induced in the guinea pig model, there is a likely synergism linking increased production of estradiol and all-trans retinoic acid with up-regulation of nuclear receptor PPARgamma and RXRalpha proteins to support tumor growth. GluR2 might be coupled to this synergism directly or via interleukin-17B, kinesin KIF5 or related genes also up-regulated in leiomyomata. GluR antagonists should be tested as inhibitors of leiomyoma growth.
Biochemical and Biophysical Research Communications 01/2004; 312(1):249-54. DOI:10.1016/j.bbrc.2003.09.189 · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine if fundal pressure at the time of cesarean delivery increases the amount of transplacental microtransfusion from mother to infant.
Pregnant women undergoing cesarean delivery were randomized to the standard uterine fundal pressure at the time of hysterotomy versus no fundal pressure. Babies of patients randomized to no fundal pressure were delivered with either vacuum or forceps. The proportion of placental alkaline phosphatase between maternal and cord blood was then determined and compared between the groups.
Eighty-four women were randomized into two groups (44 in the pressure and 40 in the no pressure groups). There was no difference between the groups in demographic variables, or indications for cesarean. There was no difference in percentage of umbilical cord blood placental alkaline phosphatase between the pressure and no pressure groups (0.06 +/- 0.2 vs 10 +/- 0.29 IU, P = 0.43).
Fundal pressure at the time of cesarean delivery does not increase the amount of transplacental microtransfusion, suggesting that modifying the method of cesarean would not decrease the chances of vertical transmission in HIV positive pregnant women.
Journal of Obstetrics and Gynaecology Research 07/2003; 29(3):152-6. DOI:10.1046/j.1341-8076.2003.00092.x · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Group B streptococcus (GBS) was recognized as a major pathogen of neonatal disease in the 1970s. With a case-fatality rate of 5% to 20%, prevention of GBS neonatal disease has been an ongoing concern. The Centers for Disease Control and Prevention (CDC), and American College of Obstetricians and Gynecologists (ACOG) published guidelines for preventive strategies in 1996. These strategies, either a risk-based or a culture-based program, have been responsible for reduced incidence of GBS-newborn disease from 1.7 to 0.4 per 1,000 live births in the years 1993 to 1999. However, there has been considerable variability in practice patterns. Reanalysis now shows that a culture-based prevention strategy provides greater reduction in early-onset neonatal disease than a risk-based protocol. The CDC replacement guidelines of August 2002 recommend culture-based GBS prevention; the risk-based strategy is no longer supported. Continued efforts to eradicate GBS-newborn disease require an understanding of the pathogen, colonization, and transmission, GBS sampling and detection methods, and maternal therapy. Until a reliable vaccination against GBS is developed, prevention of neonatal GBS disease will rely upon intrapartum treatment of maternal carriers. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to define the pathogen, describe the methods of transmission and detection, and outline the current recommendations for maternal group B streptococcus therapy.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate dose variation in approximated one-quarter tablet misoprostol fragments.
Misoprostol 100 microg tablets were weighed, separated into two lots, and quartered with a razor blade or a pill cutter. Fragments were reweighed, and the misoprostol content was determined by high-performance liquid chromatography mass spectroscopy.
Fragment weights varied more when a pill cutter was used (P <.0001). Fewer pill-cutter fragments than razor-cut fragments weighed within 10% of expected (24% vs 65%, P <.0001). Misoprostol content among the fragments that were determined by high-performance liquid chromatography mass spectroscopy was 103% +/- 12% of expected (range, 73%-124%). Tablet fragments that weighed >or=27.5 mg contained misoprostol in excess of 110% of expected in seven of eight fragments, although none from fragments that weighed <or=26.5 mg did. Misoprostol was evenly distributed in all fragments that were assayed.
Misoprostol is evenly distributed among tablet fragments. Accurate low-dose misoprostol cervical ripening is possible if the tablet fragments are individually weighed.
American Journal of Obstetrics and Gynecology 10/2002; 187(3):615-9. DOI:10.1067/mob.2002.124959 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To use microarray analysis as an unbiased approach to identify genes involved in the induction and growth of uterine leiomyomata.
Screen by arrays for up to 12,000 genes in leiomyoma (L) and control myometrium (M) from nine patients.
University research laboratories.
Nine patients in the follicular and luteal phases of the menstrual cycle.
mRNA from L and M was converted to biotin-labeled cRNA and hybridized to cDNA oligonucleotide sequences on the arrays.
Greater than two-fold change in gene expression between leiomyoma and matched myometrium.
Prominent among the 67 genes overexpressed in L relative to M were dlk or Pref-1, doublecortin, JM27, ionotropic glutamate receptor subunit 2, apolipoprotein E3, IGF2, semaphorin F, myelin proteolipid protein, MEST, frizzled, CRABP II, stromelysin-3, and TGFbeta3. The genes dlk, IGF2, and MEST are paternally expressed imprinted genes, and the others are involved in tissue differentiation and growth. Prominent among the 78 genes down-regulated in L relative to M were alcohol dehydrogenases 1alpha-gamma, tryptase, dermatopontin, thrombospondin, coxsackievirus receptor, nur77, and c-kit.
Arrays offer large-scale screening of mRNA expression, which will help us differentiate between the genes and metabolic pathways necessary for leiomyoma growth and those regulating myometrial contractions.
Fertility and Sterility 08/2002; 78(1):114-21. DOI:10.1016/S0015-0282(02)03191-6 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare the efficacy of misoprostol that is administered in the buccal pouch with the intravaginal route of administration.
One hundred fifty-seven pregnant women with a singleton live gestation, Bishop score of <7, estimated fetal weight of <4500 g, and gestational age of >24 weeks were randomized to receive misoprostol that would be placed either in the buccal pouch or vagina every 6 hours. In the buccal group, after the first 2 doses of 200 microg, the dose was increased to 300 microg for the duration of the study (up to a total of 1600 microg). In the vaginal group, after the first 2 doses of 50 microg, the dose was increased to 100 microg for the duration of the study (up to a total of 500 microg). The primary outcome variable was the interval from the first dose to vaginal delivery. Power calculations indicated the need to enroll 71 patients in each arm of the study, which would allow for the detection of a 4-hour reduction in vaginal birth interval for buccal misoprostol.
The hours from drug administration to vaginal delivery were similar between the buccal and vaginal groups (23.5 +/- 20.8 hours versus 21.3 +/- 13.4 hours), respectively. Thirty-five women (63%) versus 34 women (67%) delivered vaginally within 24 hours (P = not significant). The incidence of tachysystole was higher in the buccal group, 28 occurrences (38%) versus 15 occurrences (19%; P =.01).
Buccal misoprostol is effective for cervical ripening but results in a higher incidence of tachysystole than does intravaginal administration.
American Journal of Obstetrics and Gynecology 02/2002; 186(2):229-33. DOI:10.1067/mob.2002.119630 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy of oral sulindac in low doses for prolonged duration to decrease the risk of recurrent preterm labor and extend gestation.
This was a randomized, double-blind, placebo-controlled study of patients between 24 and 34 weeks' gestation with preterm labor treated with intravenous magnesium sulfate. After successful tocolysis, patients were randomized by the pharmacy to receive either oral sulindac (100 mg) or placebo orally every 12 hours until 34 weeks' gestation. A power analysis required 43 patients in each group.
Ninety-five patients were enrolled (46 in the sulindac group, 49 controls). No significant differences were found with respect to time gained in utero (39 +/- 25 versus 45 +/- 26 days, P = .29), delivery at more than 35 weeks' gestation (61% versus 74%, P = .29), recurrent preterm labor (20% versus 18%, P = .86), birth weight (2562 +/- 623 versus 2624 +/- 543 g, P = .62), or time spent in the neonatal intensive care unit (2.8 +/- 9.2 versus 2.4 +/- 8.6 days, P = .83) for the sulindac and control groups, respectively.
The use of oral sulindac until 34 weeks' gestation after successful parenteral tocolysis failed to reduce the incidence of readmission for preterm labor.
Obstetrics and Gynecology 11/2001; 98(4):555-62. DOI:10.1016/S0029-7844(01)01491-0 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the safety and efficacy accompanying oral and vaginal misoprostol for cervical ripening.
One thousand four women with medical or obstetric indications for labor induction and unripe cervices were randomly assigned to receive oral or vaginal misoprostol. Initial doses of 200 microg oral and 50 microg vaginal misoprostol were increased to 300 microg oral and 100 microg vaginal after two doses, to a maximum of six doses. Misoprostol was given every 6 hours in both groups. We anticipated that 11% of women treated vaginally would require intervention during the ripening process. Intervention was defined as interruption of the ripening process before labor or Bishop score of 7 or a lack of response to six misoprostol doses.
Five hundred three subjects were assigned to oral and 501 to vaginal administration. Oral misoprostol was associated with significantly higher frequencies of intervention (67 [13.3%] versus 42 [8.4%], P =.01), tachysystole (114 [23.6%] versus 85 [17.6%], P =.02), and hyperstimulation (90 [18.6%] versus 66 [13.7%], P =.04). There were no significant differences in cesarean rates (147 [29.2%] versus 120 [24.0%], P =.06), mean number of misoprostol doses used (1.5 versus 1.6, P =.18), or hours from drug administration to delivery (24.5 versus 25.4, P =.77) between the oral and vaginal groups, respectively. The numbers of deliveries between the groups within 24 hours was different (271 [56%] versus 290 [60%], P =.02), oral and vaginal, respectively. No adverse neonatal outcomes were noted.
Oral misoprostol has similar efficacy as vaginal misoprostol but is associated with a higher frequency of excessive uterine contractility and intervention.
Obstetrics and Gynecology 08/2001; 98(1):107-12. DOI:10.1016/S0029-7844(01)01369-2 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to evaluate associations between chorioamnionitis and fetal growth restriction in infants enrolled in the Collaborative Perinatal Project.
A total of 2579 nonanomalous, singleton infants delivered at 28 to 44 weeks' gestation with chorioamnionitis were matched 1:3 for ethnicity, gestational age, parity, and maternal cigarette use (all of which were correlated with both chorioamnionitis and markers of fetal growth restriction) with 7732 control infants. Moderate or marked leukocytic infiltrates of the placenta defined chorioamnionitis. Birth weight, length, head circumference, weight/length ratio, ponderal index, and birth weight/head circumference ratio in the lowest 5th percentile were markers of fetal growth restriction. Placental weight and the birth weight/placental weight ratio were also evaluated.
Compared with data on matched control infants, histologic chorioamnionitis was associated with all markers of fetal growth restriction and with low birth weight/placental weight ratios (odds ratios, 1.3-1.7). The strongest associations were found at 28 to 32 weeks' gestation (odds ratios, 2.2-11). Attributable risks for several markers of fetal growth restriction exceeded 50% in infants born at <33 weeks' gestation.
Histologic chorioamnionitis is associated with multiple markers of fetal growth restriction, with stronger associations noted in prematurity.
American Journal of Obstetrics and Gynecology 11/2000; 183(5):1094-9. DOI:10.1067/mob.2000.108866 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the effect of corticotropin-releasing hormone (CRH) on the expression of the prostaglandin (PG) E(2) EP1 receptor subtype and PGE(2) production in amnion WISH cells (AWC). AWC cultures were incubated with CRH. Culture fluid was collected for PGE(2) measurement, and the cells were collected and analyzed for EP1 protein and mRNA. Immunohistochemical localization of the EP1 receptor was also performed. Incubation of AWC with CRH resulted in a dose-dependent increase (r = 0.97) in the level of EP1 receptor protein (P < 0.001). Coincubation of AWC with CRH and indomethacin resulted in the decreased production of PGE(2) while having no effect on EP1 receptor expression. A significant but not dose-dependent increase in EP1 mRNA expression was also observed (P < 0.01). Immunohistochemical evaluation verified cell membrane localization of the receptor in both stimulated and unstimulated cells and confirmed the increased expression of EP1 receptor in response to CRH. Incubation of AWC with CRH also resulted in increased culture fluid PGE(2) levels (P < 0.01). These results suggest that the role CRH plays in the initiation of labor may also involve the promotion of elevated PGE(2) levels and increased expression of the EP1 receptor in amnion.
Biology of Reproduction 01/2000; 62(1):23-6. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To visualize histochemically the prostaglandin EP1 receptor in human amnion cells and to study the effect of inflammatory cytokines, which are known to stimulate the EP1 receptor, on localization.
Immortalized amnion cells, grown on standard microscope slides and either nonstimulated (control) or stimulated by incubation in culture medium containing interleukin-1beta (25 ng/mL), interleukin-4 (50 ng/mL), or tumor necrosis factor alpha (25 ng/mL), were incubated with rabbit anti-human EP1 antibody and stained by a two-step indirect immunoperoxidase strepavidin-biotin method using horseradish peroxidase and 3,3' diaminobenzidine as the chromogen. The localization was done on ten different flasks of cells. Duplicate slides for each cytokine concentration were prepared. Negative controls for each reagent, prior blocking with 1% bovine serum albumin or 1% milk, or pretreatment with preimmune rabbit immunoglobulin G were run simultaneously. Slides were viewed by standard light microscopy with and without counterstaining with hematoxylin.
Amnion cells incubated in medium alone showed receptor localization throughout the cytoplasmic region of the cell membrane. The localization was nonuniform; a discrete unipolar region of perinuclear nonlocalization was observed. Staining occurred in widely dispersed nests. Cytokine stimulation resulted in increased intensity of staining and an increase in the size of the positive nests; however, it did not affect the discrete unipolar perinuclear region of nonlocalization.
Histochemical localization of the human EP1 receptor confirms a cytoplasmic identity and probable plasma membrane localization. Stimulation by inflammatory cytokines increases staining by recruitment of new amnion cells and appears to increase receptor density per cell.
Obstetrics and Gynecology 01/2000; 94(6):1027-32. · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uterine leiomyomata are the main indication for a hysterectomy in the United States and occur in 25% of women >35 years. Because uterine leiomyomata can form when ovariectomized guinea pigs are exposed to estradiol and retinoic acids, we tested whether human leiomyomata had high levels of retinoic acids and related nuclear receptors. Compared with normal human myometrium, leiomyomata had 3- to 5-fold higher levels of peroxisome proliferator-activated receptor gamma (PPARgamma), retinoid X receptor alpha proteins, and all-trans retinoic acid, but only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was undetectable in either leiomyomata or myometrium. PPARgamma mRNA levels were lower in leiomyomata than myometrium, but only during the luteal phase of the cycle. A PPARgamma agonist, troglitazone, was given to guinea pigs along with estradiol and all-trans retinoic acid and produced the largest leiomyomata seen to date in this model. By contrast, no tumors formed when troglitazone was given alone or with estradiol or when troglitazone was given with estradiol and 9-cis retinoic acid. New therapies for human leiomyomata may emerge by combining antagonists for PPARgamma and retinoid X receptor alpha with selective estrogen receptor modulators.
Cancer Research 11/1999; 59(22):5737-44. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the modulatory effects of interleukin (IL)-1beta and prostaglandin (PG)E2 on the PGE2 receptor subtype EP1 in amnion cell cultures.
Amnion cell cultures were incubated in increasing concentrations of (IL)-1beta or PGE2. Cultures were also incubated in high concentrations of IL-1beta and PGE2 in combination. Changes in EP1 receptor levels were evaluated by western and northern blot analysis. Culture fluid PGE2 levels were measured by enzyme-linked immunosorbent assay.
EP1 receptor protein levels decreased with increasing levels of PGE2 (r = -0.82, P < .05). EP1 receptor protein (r = 0.95, P < .05), EP1 mRNA (r = 0.95, P < .01), and culture fluid PGE2 levels (P < .01) were all increased after IL-1beta administration. EP1 receptor levels also increased approximately fourfold in response to IL-1beta incubation even in the presence of high agonist (PGE2) concentrations (P < .01).
The results of this study show that IL-1beta might be involved in infection-induced preterm labor by interfering with the normal regulation of EP1 receptor levels and with the promotion of increased PGE2 production in amnion tissue.
Obstetrics and Gynecology 02/1999; 93(1):84-8. DOI:10.1016/S0029-7844(98)00361-5 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have demonstrated a strong correlation between infection and preterm labor. Preterm delivery is also associated with high levels of cytokines and prostaglandins in amniotic fluid. The purpose of this study was to investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on the levels of cyclooxygenase, prostaglandin E2 production (PGE2), and expression of the PGE2 receptor subtype EP1 in amnion WISH cell culture. Amnion WISH cell cultures were incubated in increasing concentrations of TNF-alpha (0-50 ng/ml). Changes in cyclooxygenase and EP1 receptor proteins were evaluated by Western blot analysis. Changes in EP1 mRNA were evaluated by Northern blot, and culture fluid concentrations of PGE2 were estimated by enzyme immunoassay (EIA). EP1 protein (p<0.01), EP1 mRNA (p<0.05), cyclooxygenase-2 (COX-2) protein (p<0.001), and PGE2 concentrations (p<0.01) all increased with increasing concentrations of TNF-alpha. Changes in COX-1 protein were not observed following TNF-alpha-incubation. The results suggest that TNF-alpha may play a role in infection-induced preterm labor by its pleiotropic ability to simultaneously stimulate COX-2 activity, PGE2 concentrations, and PGE2 EP1 receptor levels in human amnion.
Journal of Interferon & Cytokine Research 01/1999; 18(12):1039-44. DOI:10.1089/jir.1998.18.1039 · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic exposure of oophorectomized guinea pigs to 17beta-estradiol causes leiomyoma formation. Our aims were to determine whether these leiomyomas can become estradiol independent after exposure to estradiol and if raloxifene inhibits leiomyoma growth when given concomitantly with estradiol.
To induce leiomyoma development, 6 oophorectomized animals received two estradiol implants for 140 days. Next, the estradiol implants were replaced with empty implants in 3 animals, whereas the other 3 received 2 new estradiol implants and raloxifene given per os 10 mg/kg per day for 60 days. Tumor size was monitored biweekly by ultrasonography.
On estradiol removal, abdominal wall leiomyomas regressed within 15 to 30 days; when estradiol implants were reintroduced, leiomyomas redeveloped. Within 30 days on raloxifene, all abdominal leiomyomas (n = 9) regressed as determined by ultrasonography and verified at laparotomy. Serum raloxifene and estradiol levels were 432 +/- 46 pg/mL and 78 +/- 13 pg/mL (mean +/- SEM, n = 3), respectively, after 60 days of treatment.
Leiomyomas did not become estradiol independent, even after long exposure to estradiol; ultrasonography allowed frequent, noninvasive assessment of leiomyoma size, and raloxifene rapidly regressed leiomyomas in this animal model.
American Journal of Obstetrics and Gynecology 12/1998; 179(5):1283-7. DOI:10.1016/S0002-9378(98)70148-6 · 3.97 Impact Factor