Genomic imprinting and b-chorionic gonadotropin.
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Animals↗
Biomedical subjects
B Gonik
Publications and source records attributed to B Gonik.
Immunomodulation of cellular cytotoxicity to herpes simplex virus infection in pregnancy by inhibition of eicosanoid metabolism.
In an effort to evaluate the relationships among pregnancy, cellular cytotoxicity and herpes simplex virus (HSV) infection, we conducted a series of experiments investigating: (1) the maternal cellular cytotoxic response to HSV infection as compared with non-pregnant hosts, (2) the influence of both cyclooxygenase and lipoxygenase products on cytotoxicity by selective inhibition of their metabolic pathways, and (3) the potential pregnancy-related differences in immune response to selective inhibition of eicosanoid metabolism. Indomethacin was used for cyclooxygenase blockade and nordihydroguaiaretic acid was used to evaluate lipoxygenase inhibition. In the non-infected animals no differences in cytotoxicity were observed between pregnant (1.5% +/- 0.7%) and non-pregnant (4.6% +/- 2.0%) groups. HSV infection increased cytotoxicity equally in both groups (pregnant: 10.6% +/- 2.0% vs. non-pregnant: 14.2% +/- 3.4%). Indomethacin did not significantly alter cytotoxicity in either the pregnant or the non-pregnant groups compared with controls (12.8% +/- 1.8% vs. 10.6% +/- 2.0% and 14.3% +/- 3.9% vs. 14.2% +/- 3.4%, respectively). In contrast, NDGA elicited a significant reduction in the cytotoxic response in both pregnant and non-pregnant hosts (6.2% +/- 1.1% vs. 10.6% +/- 2.0% and 5.7% +/- 1.1% vs. 14.2% +/- 3.4%, respectively). From our study we conclude that: (1) cytotoxicity is maintained at low levels in the absence of HSV infection, (2) HSV infection induces a significant augmentation in host cellular cytotoxicity, (3) pregnant and non-pregnant cytotoxic responses to HSV infection appear comparable, (4) indomethacin does not augment in vitro cytotoxicity to HSV infection and (5) NDGA suppresses cytotoxicity, providing evidence that lipoxygenase metabolites are essential to cytotoxic cell function.
Animals↗
Genetic imprinting in human evolution: the decisive role of maternal lineage.
The modern study of human evolution must take into account physical anthropology, which examines phenotypic expression, and molecular evolution, which examines genotypic change. Recent independent investigations have shown that the process of genetic imprinting, defined as parental-dependent transmission of genetic traits, plays a pivotal role in human evolution. We draw on data from various scientific disciplines to support the hypothesis that maternal lineage via preferential genetic contribution, plays a decisive role in this regard. This concept is of more than theoretical interest, in that, current human disease states can be better understood and studied in the context of loss of genetically-defined evolutionary advantage.
Biological Evolution↗
Intermediate cells during cytotrophoblast differentiation in vitro.
Differentiation of the human placental trophoblast cell involves a multistep process, with the generation of several distinct types of intermediate cytotrophoblast cells. Using a short term in vitro cell culture system and centrifugal elutriation, we studied the isolation and morphological and biochemical differentiation of these separated intermediate cell populations. Freshly isolated cell fractions, incubated for 24 h, are heterogeneous in their differentiation stages as determined by the secretion of the proteins chorionic gonadotropin alpha and beta, human placental lactogen, and pregnancy specific beta 1-glycoprotein. Maintenance in cell culture allows for the further differentiation of these intermediate cells and for syncytium formation. With the use of sequential trypsinizations, our data also suggest the parallel differentiation of cytotrophoblast cells into two distinct subsets: one which, through differentiation, gets committed to syncytium formation, and the other, which remains mononuclear despite high degrees of biochemical differentiation. These latter cells retain the capacity for syncytium formation when reintroduced into appropriate culture conditions. These findings refine the use of the term "intermediate cell" by previous investigators. We suggest that our in vitro system defines normal intermediate stages of trophoblast differentiation, and also serves as a model to simulate adverse conditions of syncytial degeneration or injury.
Cell Differentiation↗
Progesterone and estradiol suppress human mononuclear cell cytotoxicity.
Fetal trophoblast is generally resistant to lysis by cytotoxic cells. We hypothesized that progesterone and estrogens secreted by the trophoblast act at the choriodecidual interface where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. Using peripheral blood mononuclear cells as effector cells in a cytotoxicity assay, we evaluated the effects of progesterone, estrone, estradiol and estriol, either alone or in combination, on cellular cytotoxicity. Both progesterone and estradiol suppressed cytotoxicity in a dose-dependent manner. Estrone, estriol, pregnenolone and cholesterol had no effect. A synergistic suppression of cytotoxicity was observed when estrone, estradiol, estriol and progesterone were combined. We speculate that trophoblast production of progesterone and estradiol may be an important local immunosuppressive mechanism contributing to fetal survival.
Cells, Cultured↗
Why patients fail antibiotic prophylaxis at cesarean delivery: histologic evidence for incipient infection.
A prospective, blinded study was conducted to test the hypothesis that antimicrobial prophylaxis failure after cesarean delivery is associated with incipient infection of the uterus, as determined by histologic evaluation of bacterial invasion and acute inflammatory cell response. One hundred nineteen patients undergoing cesarean delivery and receiving antibiotic prophylaxis were included in this study. At the time of the operation, a hysterotomy biopsy was obtained for hematoxylin and eosin staining. Marked histologic differences were noted in decidual inflammation, myometrial inflammation, and myometrial polymorphonuclear cell invasion in those patients who subsequently developed endometritis (N = 7) compared with subjects without postpartum endometritis. Using two techniques for in situ identification of bacteria within myometrial tissue (acridine orange and fluorescein DNA probe to bacterial ribosomal RNA), all clinically infected parturients demonstrated large numbers of organisms in the myometrial layer of the biopsy specimen, compared with few organisms seen in a matched subset of noninfected controls. These data support the concept that incipient infection at the time of cesarean delivery may limit the effectiveness of antimicrobial prophylaxis. Use of rapid-diagnosis methodologies may allow timely identification of these at-risk patients so that therapeutic antibiotics can be initiated.
Anti-Bacterial Agents↗
Sexually transmitted viral disease in women.
During the past decade, the incidence of sexually transmitted viral diseases has increased dramatically. In many cases, diagnosis is difficult, consequences are severe, and curative therapy is not available at present. In this article, Drs Peaceman and Gonik review current evidence about sexual transmission of viruses and discuss the latest methods of diagnosis, management, and prevention.
Female↗
Increased progesterone concentrations are necessary to suppress interleukin-2-activated human mononuclear cell cytotoxicity.
Fetal trophoblast is generally resistant to lysis by cytotoxic cells. Trophoblast progesterone and estrogens may act at the choriodecidual interface, where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. However, interleukin activation of these cytotoxic lymphocytes enhances their ability to lyse trophoblast. Recent evidence suggests that immunoactivation occurs in certain aberrant pregnancy conditions, including preeclampsia. Preeclamptic placentas produce more progesterone in vitro than do normal placentas. To study the potential association between progesterone production and immunoactivation, we evaluated the immunomodulatory effect of progesterone on cellular cytotoxicity. Comparisons were made with the use of both normal and interleukin-2-stimulated peripheral blood mononuclear cells as effector cells in a cytotoxicity assay. Progesterone suppressed cytotoxicity in a dose-dependent manner. Interleukin-2 augmented cellular cytotoxicity, and higher concentrations of progesterone were required to attenuate this response. An additive suppression of cytotoxicity was also observed when estrone, estradiol, estriol, and progesterone were combined. We speculate that the higher placental production of progesterone seen in preeclampsia may be a trophoblast compensatory response to immunoactivated maternal effector cells.
Chromium↗
Natural killer cell cytotoxicity to herpes simplex virus-1-infected cells is not altered by pregnancy.
There is evidence to suggest a decrease in natural killer cell cytotoxicity during pregnancy, but information regarding immune responsiveness to actual infection is limited. An in vitro study was undertaken to examine the effect of herpes simplex virus infection on natural killer cell cytotoxicity with peripheral blood mononuclear cells from pregnant (N = 8) and nonpregnant (N = 5) women. The peripheral blood mononuclear cells were separated by Ficoll-Hypaque centrifugation. Effector cells were incubated with live herpes simplex virus-1, ultraviolet-inactivated herpes simplex virus-1, or media alone for 18 hours at 37 degrees C. K562 target cells were used in a sodium chromate release assay with an effector-to-target cell ratio of 100:1. Baseline natural killer cell values (mean +/- SE) for pregnant patients (13.4% +/- 2.4%) and nonpregnant patients (19.8% +/- 3.7%) were similar. Natural killer cell cytotoxicity was significantly increased by incubation with live virus for both pregnant (37.5% +/- 6.2%) and nonpregnant subjects (49.8% +/- 7.6%). There was no difference in mean values between media and ultraviolet-inactivated herpes simplex virus-1-exposed samples for either group. Results suggest that (1) infection with live virus, but not viral antigen alone, can augment natural killer cell response in vitro and (2) natural killer cell response to herpes simplex virus-1 infection is not altered by pregnancy.
Cytotoxicity, Immunologic↗
Shoulder dystocia recognition: differences in neonatal risks for injury.
Shoulder dystocia (SD) is an event whose current diagnostic approach is based on subjective criteria alone. Since the risk for immediate neonatal morbidity is critically linked to recognition and appropriate management of this obstetric emergency, we hypothesized that infants having injuries consistent with SD are frequently delivered without the intrapartum identification of this condition. A retrospective analysis of 26,033 vaginal births from January 1979 to April 1987 identified 162 maternal cases in which SD was diagnosed during delivery (incidence, 0.62%). Within this subset of patients, 24 neonates (15%) were identified as having either brachial plexus or fractured clavicle injuries associated with delivery. An additional 60 neonates were identified as having similar injuries immediately following delivery but without obstetric recognition of SD. Therefore 71% of all the injured infants were the product of deliveries without SD recognition. A comparison was made of maternal and neonatal variables for three groups (SD, uninjured; SD, injured; unrecognized SD, injured). The SD, injured group distinguishes itself from the other two groups by significant differences in the degree to which variables previously associated with SD are present. Conversely, both other groups are similar in all parameters except for accepted SD maneuvers utilized. These results support our hypothesis that SD is underreported in the obstetric literature and that unrecognized SD is associated with an increased risk of neonatal injury. Efforts to define objectively the threshold forces associated with neonatal injury and to develop SD teaching models should improve this clinical dilemma.
Adult↗
Evaluation of phenazopyridine hydrochloride as a tool in the diagnosis of premature rupture of the membranes.
This is a prospective study to determine whether a maternal orally administered azo dye, phenazopyridine hydrochloride, would cross into amniotic fluid, and thus be of potential aid in the diagnosis of rupture of the membranes. Based on anecdotal experience, we hypothesized that this compound would cross the placenta and be excreted in the fetal urine, causing discoloration of the amniotic fluid. Ten patients with uncomplicated pregnancies undergoing elective amniocentesis for obstetric indications received an oral dose of 400 mg of phenazopyridine hydrochloride 4 hours prior to the procedure. Amniotic fluid was also available from five control patients who did not receive phenazopyridine hydrochloride. The typical orange-to-red discoloration of the urine was seen in all study patients, indicating ingestion of the dye. None of the ten patients had evidence of the azo dye in their amniotic fluid by visual inspection or by spectrophotometric absorbance. After the amniotic fluid samples were acidified, the presence of the azo dye was visually demonstrable, and spectrophotometry confirmed measurable concentrations (mean +/- SE: 13.08 +/- 0.72 micrograms/ml). We conclude that although phenazopyridine hydrochloride does cross the placenta into the fetal compartment, its presence causes a visual and spectrophotometric change in the color of amniotic fluid only when the normal basic pH of amniotic fluid is acidified.
Amniotic Fluid↗
General precepts of the immunology of pregnancy.
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Female↗
Comparison of two enzyme-linked immunosorbent assays for detection of herpes simplex virus antigen.
Two enzyme-linked immunosorbent assays (ELISAs) for herpes simplex virus (HSV) detection were compared with culture in a prospective, blinded study with 153 patients with suspected recurrent oral or genital HSV. A subset of 15 of these subjects were studied daily until symptom resolution during a single episode of recurrent HSV. Direct-site specimens were collected and either placed in viral transport media (for Ortho ELISA and fresh inoculation into primary rabbit kidney cells) or frozen in ELISA collection media (DuPont). One hundred eighty-six culture-ELISA comparisons were analyzed. On the basis of culture positivity, the DuPont and Ortho ELISAs differed substantially with regard to sensitivity (93 versus 35%) but had similar specificities (95 versus 100%) and positive (85 versus 100%) and negative (98 versus 85%) predictive values. There were seven DuPont ELISA-positive, culture-negative samples which were confirmed positive for HSV by blocking antibody test (revised specificity, 100%; positive predictive value, 100%). Six of these discrepant samples were from previously culture-positive subjects. These results demonstrate that currently available ELISA kits vary substantially as to their sensitivities in detecting HSV antigen from direct-site specimens. In addition, antigen detection, by ELISA technology, is not always synonymous with state of viral infectivity as judged by tissue culture cytopathic effect.
Antigens, Viral↗
Induction of cytokines in normal placental cells by the human immunodeficiency virus.
Placental cotyledon mononuclear cells (CMC) resemble peripheral blood monocytes/marcophages (MM) with respect to their expression of surface antigens and cellular function. CMC also express the CD4 antigen receptor and are thus susceptible to infection with the human immunodeficiency virus (HIV). When vertical transmission of HIV from mother to fetus occurs, the infection often remains latent until appropriate factors initiate the transcription of virus-specific mRNA. Cytokines, such as interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) which are produced by MM, up-regulate HIV expression in infected cells. The induction of cytokines in MM does not require active infection with HIV since heat-inactivated HIV (iHIV) and envelope gp120 caused cytokine secretion. We studied the ability of CMC from normal placentas to secrete these cytokines following stimulation with endotoxin, iHIV, recombinant GP160 and GAG55, and synthetic p17, HGP-30. Whereas CMC spontaneously secreted low levels of IL-1 beta and TNF-alpha, they constitutively secreted high levels of IL-6. All cytokine levels could be boosted by endotoxin. GP160, iHIV, and HGP-30 failed to augment cytokine levels above baseline. In contrast, GAG55 significantly boosted only TNF-alpha. The relevance of these findings is discussed with respect to the putative roles of cytokines in the immunoregulation of HIV in utero.
Cell Transformation, Viral↗
Risk factors for shoulder dystocia: an engineering study of clinician-applied forces.
We report on engineering risk factors associated with clinician-applied forces during vaginal delivery of newborns. Specifically, we present and interpret data from a series of experiments using force-sensing devices on 29 randomly selected vaginal births, including two shoulder dystocia deliveries and one birth injury. The results indicate that clinician-applied peak forces are typically about 47 N for routine deliveries, 69 N for difficult deliveries, and 100 N for a shoulder dystocia delivery (P less than .01). The time required to deliver fetal shoulders doubles for nonroutine deliveries (P less than .01). In addition, impulse and rate of application of force distinguish between routine and nonroutine deliveries (P less than .03). We conclude that, if properly perceived, force, force rate, and the duration of force are objective parameters that can be used in recognizing and managing shoulder dystocia and in predicting thresholds for birth injury.
Biophysical Phenomena↗
Multicenter clinical evaluation of the Du Pont Herpchek HSV ELISA, a new rapid diagnostic test for the direct detection of herpes simplex virus.
A new 4h rapid enzyme-immunoassay for direct detection of herpes simplex virus (HSV) antigen (Du Pont Herpchek) was evaluated with 743 clinical samples collected at obstetrics and gynecology (OB/GYN), sexually transmitted diseases (STD), and ophthalmology clinics. The sensitivity and specificity of Herpchek was 98.0% and 98.4% respectively compared to virus isolation in cell culture. Confirmatory blocking ELISA tests, clinical history and follow up indicate that the true specificity of the test is 100%.
Adult↗
Immune modulation of natural killer cell cytotoxicity against herpes infected target cells in pregnancy.
Natural killer cell cytotoxicity (NKC) is a nonspecific, primary immunodefense system active against a variety of pathogens, including herpes simplex virus (HSV). Evidence suggests that during pregnancy, NKC is attenuated. The regulatory mechanisms for this immune attenuation have yet to be defined. We examined two cytokines (interleukin-2 [IL-2] and alpha interferon [IFN]) for their ability to alter NKC responsiveness during pregnancy, utilizing an HSV-infected target cell model. Peripheral mononuclear effector cells were isolated from 19 pregnant and 19 nonpregnant subjects by Ficoll-Paque separation. These cells were incubated with IFN, IL-2, or media alone, and analyzed for %NKC by an 18 h chromium release assay. The percentage of NKC was lower using the effector cells from the pregnant subjects as compared to nonpregnant controls. Incubation with either IFN or IL-2 resulted in a significant augmentation of NKC in both the pregnant and nonpregnant derived cells. There were no differences in IL-2 dose requirements or levels of cytotoxicity achieved (43.1 +/- 6.8% vs. 44.4 +/- 6.8%, respectively) between pregnant and nonpregnant derived cells. The IFN-mediated augmentation of NKC was somewhat blunted in pregnancy both in terms of absolute levels of cytotoxicity achieved (26.1 +/- 3.9% vs. 37.2 +/- 4.9%, respectively) and dose response curves generated. These results demonstrate that NKC against HSV infected cells is attenuated during pregnancy and can be immunoregulated with the use of either IFN and IL-2. The restoration of NKC responsiveness with IFN, however, remains incomplete during pregnancy, suggesting that this cytokine's mechanism of action differs from that of IL-2.
Antigens, CD↗