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V Toder

Publications and source records attributed to V Toder.

At least 55 records · Page 3Linked to original sources
PubMed1996

Teratogen-induced apoptosis may be affected by immunopotentiation.

Intra-uterine immunization of mice with paternal allogeneic or xenogeneic (rat) splenocytes was found to increase embryo tolerance to cyclophosphamide (CP)-induced teratogenesis. As the CP-induced teratogenic effect was shown to be associated with apoptosis, the present study was designed to investigate whether the protective effect of immunopotentiation may be realized via an alteration of CP-induced apoptosis. Various doses of CP were injected intraperitoneally into ICR mice on day 12 of pregnancy. Intra-uterine immunization with xenogeneic rat splenocytes was carried out 3 weeks before mating. Implantation sites, resorptions, live and dead fetuses, as well as soft tissue anomalies and external malformations, were recorded to evaluate the CP-induced embryotoxic effect. In parallel, flow cytometric analysis and DNA fragmentation assay were used for evaluation of CP-induced apoptosis in limbs, tail and whole embryos. The treatment of mothers with a high dose of CP induced the death of almost all embryos and striking fetal growth retardation in survivors. This strong embryotoxic effect was accompanied by very prominent DNA degradation in cells collected from whole embryos. Immunostimulation caused a dramatic decrease of embryonal loss (by approximately 50%) and a significant (about 30%) increase in fetal weight. Such an increase in fetal survival and in fetal weight was found to be accompanied by a clear decrease in apoptosis level in embryo cell population as judged by DNA gel electrophoresis with subsequent quantitation of DNA fragmentation in negatives by an image analysis technique. After treatment with a low dose of CP, a decrease in the proportion of fetuses with limb and tail anomalies in immunized females was accompanied by a decrease in the proportion of apoptotic nuclei in cells taken from limbs and tails. The results of this study suggest that the teratogen-induced apoptosis may, at least partly, be dependent on fetomaternal immune interactions.

Adjuvants, Immunologic↗
PubMed1996

Intravenous immunoglobulin in women with five or more abortions.

PROBLEM: Treatment for recurrent miscarriage has usually been given to all women with three or more abortions of unknown cause. As these patients have a 50-60% subsequent live birth rate, no treatment has been shown to unequivocally improve the live birth rate. Immunoglobulin is the latest treatment to be applied. In order to determine if immunoglobulin improves the live birth rate, we analyzed the results of patients expected to have a poor outcome in the subsequent pregnancy if left untreated, i.e., women with five or more abortions, who have aborted after paternal leucocyte immunization or who continue to abort despite possessing anti-paternal complement dependent antibody (APCA). METHODS: A preliminary trial was carried out using immunoglobulin (Sandoglobulin, Sandoz, Switzerland). It was infused at a dose of 400 mg/Kg body weight, in the follicular phase of a cycle in which pregnancy was planned. A booster dose was administered as soon as pregnancy was diagnosed. RESULTS: Twelve patients were treated, ten conceived. Five have had subsequent live births. Two infants were premature but their size was appropriate for gestational age. The other three infants delivered at term. CONCLUSIONS: This is still too small a group from which to draw definite conclusions about the efficacy of immunoglobulin to prevent abortion. However, five live births in ten patients is an encouraging result, especially when the expected poor obstetric outcome is considered. Hence the efficacy of immunoglobulin should be evaluated further in high risk patients.

Abortion, Habitual↗
PubMed1996

Anti-Mac-1 antibodies and early pregnancy loss in mice.

This study focused on the role of adhesion molecules in early pregnancy in mice. Injection of anti-Mac-1 antibodies during early pregnancy resulted in early pregnancy loss (only 30.7% of mice in the group injected with anti-Mac-1 antibody were pregnant compared with 87.5% of controls), while mice treated with anti-Mac-1 antibodies during late pregnancy did not show a significant abortive effect (68.8% mice in the treated group were pregnant compared with 92.9% of control mice). Anti-LFA-1 alpha, LFA-1 beta or mouse Ag-Eb antibodies, when injected during early pregnancy, caused a nonsignificant decrease in pregnancy rate ranging between 15% and 25% (P > 0.05), while anti-Thy-1.2 antibodies demonstrated a marginal effect only. Staining of uterine tissue sections, collected on days 4-6 of pregnancy, with anti-Mac-1 antibodies, demonstrated antibody bound to cells in the deep endometrium and in the myometrium but not in the uterine area close to the lumen or on the surface of the blastocyst. These results indicate a possible role for the Mac-1 antigen in early pregnancy.

Abortion, Spontaneous↗
PubMed1996

The effect of cyclophosphamide on rat blastocysts in vitro and their subsequent development following transfer to pseudopregnant rats.

These investigations were undertaken to assess the effects of cyclophosphamide (CPA) on rat blastocysts. In the first set of experiments, blastocysts were exposed to 100 micrograms/ml CPA in culture for 48 h. In the second experiment, blastocysts were cultured for 48 h following injection of 20 or 40 mg/kg of CPA to pregnant rats on day 4 of gestation. In the third experiment, blastocysts were cultured for 2 h in the presence of 100 micrograms/ml of CPA and then transferred to pseudopregnant rats. The results from the first experiment revealed a clear toxic effect of CPA on blastocysts following culture. A similar effect occurred when blastocysts were harvested and cultured following in vivo injections of CPA. In the third experiment a clear embryotoxic effect (larger number of resorptions and retarded embryos in comparison to control) was found on day 13 of gestation. The origin of activation of CPA by the blastocysts could not be ascertained from the above results.

Animals↗
PubMed1995

Cyclophosphamide-induced teratogenesis in ICR mice: the role of apoptosis.

It is known that programmed cell death (apoptosis) is an important physiological determinant of embryonic development. In parallel, it may be one of the major events involved in induced teratogenesis. The present study was designated to evaluate to what extent is apoptosis involved in the formation of some final abnormalities induced by cyclophosphamide (CP) in ICR mice. The level of apoptosis in limbs, tail, liver, and whole embryo was assessed 24 h after administration of various doses of CP (day 12 of pregnancy) by flow cytometric analysis and by DNA fragmentation assay. In parallel, the rate of limb and tail malformations, resorptions, and growth retardation induced by various doses of CP was evaluated in animals sacrificed on day 19 of pregnancy using routine teratological methods. A striking correlation between the rate of CP-induced apoptosis in limb and tail cells and the severity of limb and tail anomalies was found after administration of CP ranging from 10 to 40 mg/kg. Thus, the percent of apoptotic cells collected from limbs and tails increased from 18 to 78%. In parallel, the severity of limb and tail anomalies increased from digit anomalies to amely and from crooked to short or absent tail. CP-induced embryolethality and fetal growth retardation also correlated with the level of apoptosis in cells collected from whole embryos but to a lesser extent. These results claim that CP-induced apoptosis is one of the inevitable events in the pathway leading to the formation of CP-induced abnormalities and also suggest that the extent of the involvement of apoptosis in the formation of different types of final abnormalities, may be different.

Abnormalities, Drug-Induced↗
PubMed1995

Pregnancy-associated effect on mouse thymocytes in vitro.

Thymic involution during pregnancy is a phenomenon which has been described for a long time in various mammalian species but its significance for the success of pregnancy in not yet known. Consequently, we have studied the effect of placental cells on functional activity and cell surface antigen expression of thymocytes in combination with the thymic stroma. Trophoblast cells inhibited almost completely the proliferative response of thymocytes whether or not combined with the thymic stroma. Decidual cells were also found to have an inhibitory effect on thymocytes proliferation while their combination with the thymic stroma decreased the thymocyte proliferation rate almost completely. Both decidual and trophoblast explants in combination with the thymic stroma increased CSF production by the thymocytes while inhibiting IL-6 production. Also, both trophoblast and decidual cells caused no significant changes in the expression of Thy-1, CD5, CD4, CD8, CD3, CD25, CD44, and L-selectin by the thymocytes. Comparable results were obtained for lymph node cells in terms of both proliferation and cell surface antigen expression, except for a trophoblast-dependent decrease in L-selectin expression. These results suggest a possible role for placental cells in immunoregulation of functional activity of thymocytes, which might represent one of the mechanisms mediating pregnancy-associated thymic involution in vivo. However, no correlation between thymocytes functional activities and changes in their cell surface antigen expression could be established.

Animals↗
PubMed1995

Evaluation of serum-associated embryotoxicity in women with reproductive disorders.

PURPOSE: Our purpose was to determine whether some cases of infertility may be due to serological factors inhibiting development of the embryo. METHOD: We examined the effect of infertile women's sera on the expansion, attachment, and spreading of mouse blastocysts in culture. Cell marker expression was also assayed by an indirect immunofluorescence technique. Serum samples from 75 infertile women were compared to the effect of 24 control AB sera. RESULTS: After 72 hr, blastocyst spreading was significantly different depending on whether cultured in sera from women with unexplained infertility, anovulatory infertility, diethylstilbesterol exposure or controls. Neither sera from women with mechanical infertility (14) nor sera from women with endometriosis (8) affected blastocyst growth in culture. CONCLUSIONS: Inhibitory sera were capable of reducing cytokeratin expression but had no effect on placental alkaline phosphatase or concanavalin A expression by blastocyst cells. It can be inferred that the inhibitory effect of sera from women with certain types of infertility might be due to damage to the cytoskeleton. This in vitro assay may predict the success or failure of IVF.

Adult↗
PubMed1995

Immunoteratology: I. MHC involvement in the embryo response to teratogens in mice.

PROBLEM: The present study was carried out to evaluate an involvement of MHC-associated maternal immunoreactivity in response to environmental teratogens. METHODS: Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol, 1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in syngeneically and allogeneically mated CBA/J and C57B1/6 mice. In part of C57B1/6 female mice, paraaortic lymph nodes were extirpated 14 days before mating to allogeneic or syngeneic males. Twenty or 40 mg/kg of CP or 300 or 600 mg/kg of QD were injected on day 12 and 9 of pregnancy, accordingly (vaginal plug indicates day 1 of pregnancy). On day 19 of pregnancy implantation sites, resorption, live and dead fetuses were recorded and live fetuses were examined with methods routinely used in applied teratology. RESULTS: Both mice strains showed equal response to teratogens but the RT-induced effect was significantly weaker in allogeneic than syngeneic mouse combinations. Extirpation of draining lymph nodes dramatically increased the sensitivity to RT in allogeneically mated females but failed to alter that of syngeneically mated ones. CONCLUSION: The results of this study suggest that fetomaternal MHC incompatibility exerts the favourable influence on teratological resistance of the embryo and MHC-associated immunoreactivity of "mother-fetus" axis is possibly responsible for this effect.

Abnormalities, Drug-Induced↗
PubMed1994

MHC-associated immunopotentiation affects the embryo response to teratogens.

The present study was performed to evaluate whether the effect of environmental teratogens can be modified by maternal immunostimulation. Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol,1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in two animal models: (i) primigravid C57Bl/6 mice who underwent intrauterine immunization with allogeneic paternal (CBA/J), third-party (BALB/c) or syngeneic male splenocytes 21 days before mating; (ii) C57Bl/6 and CBA/J mice who were treated with RT during the second pregnancy only, after a different mating combination (syngeneic or allogeneic) in the first and the second pregnancy. Different doses of CP and QD were injected on days 12 and 9 of pregnancy, respectively. On day 19 of pregnancy implantation sites, resorptions, live and dead fetuses were recorded and live fetuses were examined for external and internal malformations with methods routinely used in teratological study. It was shown that intrauterine immunopotentiation with allogeneic paternal splenocytes clearly enhances the tolerance of F1 embryos to RT. Thus, in CP-treated females the resorption rate and the proportion of malformed fetuses were significantly reduced. It was followed by an almost two-fold increase in fetal weight. The protective effect of such immunization in QD-treated females was manifested as a dramatic decrease of the proportion of malformed fetuses and the resorption rate. Syngeneic splenocytes could not significantly influence an embryo's sensitivity to RT. The response to RT was also significantly weaker in the second pregnancy of female mice mated twice allogeneically than that observed in allogeneically mated primigravid mice. These results show that the embryo's response to environmental teratogens may be influenced by fetomaternal immune interactions.

Abnormalities, Drug-Induced↗
PubMed1993

Congenital malformations after immunotherapy for habitual abortion: is there an increase?

The risk of congenital malformations as assessed in infants born to women who underwent immunotherapy for habitual abortion. One hundred and eighty women were immunized with paternal mononuclear cells and 85 were not. Of 135 pregnancies in immunized patients, 27 (20%) were miscarriages, and 4 of the remaining 108 had congenital malformations. Two (encephalocele and common AV canal) were diagnosed in the 20th and 21st week of gestation. A case of esophageal atresia and Fallot's tetralogy were diagnosed at birth. Of 65 pregnancies in the non-immunized group 38 (58.5%) were miscarriages, and of the remaining 27, 1 case of Down's syndrome occurred. In a subgroup of 7 habitually aborting couples with parental balanced chromosomal anomalies, the balanced translocation was transferred to the infant in 1 case. No other congenital anomalies were found in either group. Consequently, these anomalies are probably not the result of abnormal pregnancies retained as a result of immunization.

Abortion, Habitual↗
PubMed1993

Lupus anticoagulant. Significance in habitual first-trimester abortion.

Therapy with steroids and aspirin has been reported to benefit pregnancies in patients with lupus anticoagulant (LA). In this study, habitual first-trimester aborters with LA using steroids and aspirin were compared to a control group of untreated habitual aborters without LA. In habitual aborters with LA, 12 of 24 (50%) pregnancies reached the second trimester as compared to 8 of 22 pregnancies (36%) in the control group. Since the treated group did no better than the control group, LA probably is not a cause of first-trimester abortion. However, once the second trimester is reached, a 50% incidence of growth retardation was found, and 42% of fetuses died in the second or third trimester in treated LA patients. Treatment with steroids and anti-platelet aggregating agents may be necessary despite the attendant risks to prevent those sequelae in the second and third trimesters. There was a 29% live birth rate in treated LA patients; the rate was 36% in control patients. However, this rate was produced only by early intervention, which was unnecessary in the control patients.

Abortion, Habitual↗
PubMed1993

The difference between septated and nonseptated nuchal cystic hygroma in the early second trimester.

OBJECTIVE: To compare nonseptated and septated cystic hygromas in terms of morphologic appearance and prognosis. METHODS: During a 5-year period, 125 cases of nonseptated cystic hygroma were detected by transvaginal sonography among 7582 sonographic fetal scans (1.6%) in the first and early second trimesters. Twenty-five cases of septated cystic hygroma were detected in the same population. Fetal karyotype abnormalities; sonographic, morphologic, and histologic appearance; and pregnancy outcome were compared between the groups. RESULTS: Whereas 98% of the nonseptated cystic hygromas were transient, only 44% of the 25 septated cystic hygromas were transient. Six of the 106 cases of nonseptated cystic hygroma that underwent karyotyping were dyskaryotic (5.7%), compared with a 72% (18 of 25) aneuploidy rate in the septated cystic hygromas. Only two cases of hydrops fetalis (1.7%) occurred among the nonseptated cystic hygromas, versus 40% (ten of 25) in the septated cystic hygromas. Fifteen percent of the nonseptated cystic hygromas had associated anomalies (17 of 115) versus 52% (13 of 25) in the septated counterpart. As compared with the septated group, the nonseptated cystic hygromas had a different sonographic, morphologic, and histologic appearance. The live-birth rate was 94% (108 of 115) in the nonseptated cystic hygromas, versus only 12% in the septated group. CONCLUSIONS: This study confirms our previous suggestion that nonseptated cystic hygromas differ from septated lesions, not only in location and morphologic appearance, but also in prognosis.

Adult↗