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Biomedical subjects

M Vignali

Publications and source records attributed to M Vignali.

At least 37 records · Page 2Linked to original sources

Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate.

The present study was conducted to investigate whether GnRH-receptor (GnRH-R) gene is expressed in endometriosis ovarian implants and whether a GnRH-analogue (GnRH-a) may exert an effect on endometriosis cell proliferation in vitro. The presence of GnRH-R transcripts in ovarian endometriosis cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and further confirmed by Southern blot analysis. GnRH-R mRNA was detected in all the 13 samples examined. In contrast, GnRH-R transcripts were not detectable in endometriosis-free peritoneal tissue. In the second part of the study, endometriosis cells were cultured for 9 days with different doses of leuprolide acetate (ranging from 0 to 10(-5) M). In 4 out of 13 cases, a significant anti-proliferative effect was observed at doses of leuprolide acetate ranging from 10(-9) to 10(-5) M. In one case, a significant inhibition of cell proliferation was observed only at 10(-5) M leuprolide acetate concentration. In contrast, the GnRH-a did not affect cell growth, regardless of the expression of GnRH-R transcripts and the given doses, in the remaining 8 experiments. To date, this is the first evidence indicating that GnRH-R mRNA is expressed in human ovarian endometriomas. Moreover, the inhibition of endometriosis cell proliferation induced by the GnRH-a in vitro suggests that, at least in some cases, this compound might exert a direct effect on endometriosis lesions.

Adult↗

Unexplained habitual abortion is associated with a reduced endometrial release of soluble intercellular adhesion molecule-1 in the luteal phase of the cycle.

Although the mechanisms causing recurrent spontaneous abortion (RSA) remain frequently speculative, recent evidence indicates that a specific uterine immune-endocrine network plays a pivotal role in the continuation of pregnancy. We have recently demonstrated that an adhesion molecule of the immune system, named intercellular adhesion molecule (ICAM)-1, is markedly expressed at both protein and mRNA levels in endometrial stromal cells and is able to mediate their interaction with lymphoid cells. Moreover, we have shown that the soluble form of ICAM-1 (sICAM-1) can be released by the endometrium in a hormone-dependent manner. The present study was designed to determine whether surface and/or sICAM-1 expression by cultured endometrial stromal cells could be related to early pregnancy loss in patients with a history of unexplained RSA. Luteal-phase endometrial biopsies were obtained from eight patients who had experienced three or more consecutive unexplained RSAs in the first trimester and 12 control fertile women. Surface ICAM-1 was similarly expressed on luteal-phase endometrial cells obtained from women with and without a history of unexplained RSA. In contrast, the endometrial release of sICAM-1 was significantly lower in abortion-prone patients than in control women. sICAM-1 is a cytokine-inducible molecule able to interfere with several immunological responses and the reduced levels of the protein shed by the endometrium in patients who have suffered from unexplained RSAs may reflect the presence of an altered immunological environment during the early phases of pregnancy.

Abortion, Habitual↗

Endometrial release of soluble intercellular adhesion molecule 1 and endometriosis: relationship to the extent of the disease.

OBJECTIVE: To relate endometrial release of the soluble form of intercellular adhesion molecule 1 with extent of endometriosis. METHODS: Samples of endometrium were collected from 23 women with endometriosis. Soluble intercellular adhesion molecule 1 was quantified in conditioned medium from 48-hour endometrial stromal cell cultures with use of a specific enzyme-linked immunosorbent assay. Levels were correlated with revised American Society for Reproductive Medicine classification score for adhesions, implants, and cysts and total score; number of endometriotic implants; cyst diameter; and presence or absence of pelvic pain symptoms and previous surgical procedures for endometriosis. RESULTS: Endometrial release of soluble intercellular adhesion molecule 1 directly correlated with number of implants (r = .64, P < .005) and score for implants (r = .61, P < .005). There was no significant correlation between levels of the soluble molecule and score for adhesions or total score. Soluble intercellular adhesion molecule 1 shed by endometrium did not correlate with the score for ovarian cysts, although an inverse relationship was found with ovarian cyst diameter (r = -0.52, P < .05). No differences were detected between women who had pelvic pain and those who did not and between those who had previous surgery for endometriosis and those who had not. CONCLUSION: The association between endometrial release of soluble intercellular adhesion molecule 1 and the number and score of endometriotic implants suggests that the molecule might be of value in evaluating spread potential of refluxed endometrium.

Adult↗

Adequate timing of fetal ultrasound to guide metabolic therapy in mild gestational diabetes mellitus. Results from a randomized study.

BACKGROUND: Ultrasound assessment of abdominal circumference early in the third trimester had been proposed to introduce insulin therapy in order to prevent fetal overgrowth in women with mild gestational diabetes mellitus. The purpose of this study was to investigate adequate weeks gestation timing for testing this parameter. METHODS: One hundred and forty-one women were included in a randomized trial. Seventy-three women were evaluated at both 28 and 32 weeks gestation whereas 68 women were investigated only at 32 weeks gestation. In both groups, insulin therapy was promptly started when abdominal circumference exceeded the 75th percentile. Macrosomic rates were compared using the Fisher's exact test. RESULTS: Twenty-nine women whose fetal abdominal circumference exceeded the 75th percentile were considered eligible for insulin therapy. In this group, we observed a statistically significant increase in the percentage of macrosomic infants born from women whose ultrasound abdominal circumference assessment was performed only at 32 weeks gestation when compared to women evaluated at both 28 and 32 weeks gestation (71.43% vs 33.33%, p<0.05). CONCLUSIONS: Our results support the need for fetal ultrasound at 28 weeks gestation to direct metabolic therapy since insulin administration introduced after 32 weeks gestation has a poor effect on fetal growth.

Abdomen↗

[Efficacy of the vaginal administration of natural progesterone in patients with recurrent spontaneous hormone caused abortion].

AIM: The study aimed to demonstrate that, owing to a documented luteal phase deficiency, natural progesterone treatment improves expectations for the continuity of pregnancy in patients with a high risk of spontaneous abortion in the first trimester. The endovaginal administration of this hormone in women suffering from multiple abortions during the first trimester may improve the prognosis in terms of the continuation of the pregnancy beyond the 12th week of gestation. METHODS: A study was carried out to compare two groups of patients: a group consisting of 19 patients underwent natural progesterone treatment in the form of a vaginal cream (ESOLUT) at a dose of 100 mg a day. The second group, consisting of 15 patients, formed a control group and did not receive any additional progestin treatment. The study was carried out between May 1998 and August 1999 at the 2nd Clinic of Obstetrics and Gynecology at the University of Milan, in the Clinica "L. Mangiagalli", on a total of 34 patients suffering from recurrent spontaneous abortion during the first trimester and luteal phase deficiency. No other risk factors for abortion were noted at the initial screening. The deficiency was confirmed during screening using three blood samples assayed for plasma progesterone during the second phase of the menstrual cycle. In order to make a diagnosis of luteal phase deficiency, at least one of the three values had to be less than 10 ng/ml. These patients (19) received additional endovaginal progesterone therapy. RESULTS: A lower incidence of spontaneous abortion during the first trimester was noted at the end of the study in treated patients compared to the control group (21% vs 16%). CONCLUSIONS: These results lead us to conclude that natural progesterone treatment in patients with a confirmed hormone deficiency during the luteal phase does not reduce the risk of abortion in the overall population of pregnant women, but improves the prognosis compared to the group of women suffering from multiple abortions, thereby reducing the risk to that in the general population.

Abortion, Habitual↗

Follow-up of laparoscopic treatment of stage III-IV endometriosis.

STUDY OBJECTIVE: To evaluate the efficacy of conservative laparoscopic surgery in a series of patients with stage III-IV endometriosis. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: All 141 women who underwent conservative operative laparoscopy for stage III-IV endometriosis between January 1993 and December 1996 and were followed for a minimum of 6 months. INTERVENTIONS: Laparoscopic procedures performed with scissors, bipolar coagulation, and hydrodissection. MEASUREMENTS AND MAIN RESULTS: Clinical examination, transvaginal ultrasonography, and pain questionnaire were scheduled every 6 months postoperatively. The cumulative proportion of pregnant patients and cumulative recurrence rate were calculated by Kaplan-Meier method. Twenty-five women (44%) with infertility became pregnant. Twenty-three (51%) had stage III and two (16.7%, p <0.05) had stage IV endometriosis. The 24-month cumulative pregnancy rate was 57.5%. Thirty-one women (22%) reported pain recurrence during follow-up. Five (3.5%) recurrences were confirmed by histologic examination and eight (5.7%) were documented only by clinical and ultrasonographic findings. No recurrence occurred in the first 6 months of follow-up. CONCLUSION: Operative laparoscopy seems to be effective treatment for stage III endometriosis. A larger series with longer follow-up is necessary to clarify its role in the management of stage IV disease. (J Am Assoc Gynecol Laparosc 6(1):55-58, 1999)

Adult↗

Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis.

Immune dysfunctions in endometriosis are widely documented but the effectiveness of immunotherapies for the management of the disease is still debated. Progress in this field has also been limited by the lack of an appropriate animal model of the disease. In this study, we created a model of endometriosis in immunocompetent mice to verify the ability of endometrium to implant in ectopic sites and to investigate the potential application of the cytokine interleukin (IL)-12 in preventing this ectopic implantation. Endometriotic lesions were induced in both C57BL/6 and BALB/c mice by inoculating syngenic endometrial fragments through a small laparotomic incision into the peritoneal space. All the animals challenged with syngenic endometrium showed evidence of peritoneal endometriosis at 3 weeks. Histologically, endometriotic lesions consisted of cystic endometrial glands surrounded by a stroma. Intraperitoneal injection of IL-12 was able to reduce total weight and total surface area of endometriotic lesions respectively of 77 and 61% in C57BL/6 and of 42 and 28% in BALB/c mice. These results demonstrate that IL-12 is able to induce a significant prevention of ectopic endometrial implantation in an in-vivo model of endometriosis. These findings support the possibility of using the immune system to generate novel therapies for the management of the disease.

Adjuvants, Immunologic↗

Effects of 3 month therapy with danazol after laparoscopic surgery for stage III/IV endometriosis: a randomized study.

The effect of treatment with danazol was evaluated with respect to expectant management after laparoscopic conservative surgery. All patients conservatively operated at laparoscopy for stage III-IV endometriosis from July 1994 to October 1996 were requested to enter the study. Patients who underwent surgery for recurrent endometriosis were excluded from the study, as well as patients who had taken hormonal therapies before laparoscopy. Informed consent was obtained from 77 women who were randomized after surgery to treatment with danazol 600 mg daily for 3 months (n = 36) or to expectant management (n = 41). All patients were regularly followed up every 6 months for evaluation of fertility, recurrence of pain symptoms and disease. During the follow-up, six (55%) of the 11 infertile women allocated to danazol and eight (50%) of the 16 given no treatment became pregnant (not significant). Moderate/severe pelvic pain recurred during follow-up in seven (23%) of the 31 women with pelvic pain allocated to the danazol group and nine (31%) of the 29 allocated to no treatment; the respective cumulative pain recurrence rates at 12 months were 26 and 34% (log rank test, not significant). Three women (8.3%) treated with danazol and six (15%) who received no treatment had disease recurrence as demonstrated by gynaecological examination and/or pelvic ultrasonography (not significant). Our results do not demonstrate a significant advantage of 3 month danazol therapy after laparoscopic surgery for stage III-IV endometriosis with respect to postoperative expectant management.

Adult↗

Blood flow in the internal carotid and middle cerebral arteries: effects of continuous oral conjugated equine estrogens administration with monthly progestogen supplementation on postmenopausal women.

OBJECTIVE: This study was designed in order to evaluate the effect of conjugated equine estrogens (CEE) on internal carotid and middle cerebral artery blood flow in postmenopausal women. DESIGN: Thirty-four healthy postmenopausal women with intact uteri were randomly divided into two groups of 17 subjects each. The first group was treated for 24 weeks with continuous CEE medication (0.625 mg daily) and cyclical supplementations of 5 mg/day of medrogestone acetate, given on the last 12 days of every 4-week period (Prempak, Wyeth, Italy). The second group received no treatment. The pulsatility indices (PI) of both the internal carotid artery and middle cerebral artery were measured. RESULTS: In the treated group, the PI of the interior carotid artery and MCA was reduced from respectively 0.736 (0.016) and 0.745 (0.009) at baseline, to 0.669 (0.021) and 0.670 (0.011) after 24 weeks (p = 0.01); in the control group, the PI values remained unchanged. The between-group difference for both arteries was significant (p < 0.01). CONCLUSIONS: The administration of CEE with cyclical medrogestone supplementation to postmenopausal women induces a statistically significant reduction in the PI of cerebral arteries.

Administration, Oral↗

Laparoscopic excision of ovarian dermoid cysts with controlled intraoperative spillage. Safety and effectiveness.

OBJECTIVE: To compare the operative and postoperative course in patients undergoing laparoscopy for dermoid cyst to that observed in subjects with other types of ovarian masses and of patients undergoing laparotomy for teratomas. STUDY DESIGN: Retrospective analysis. From 1994 to 1996, 49 women underwent laparoscopic cystectomy for dermoid cysts. The operative and postoperative course was compared to that of 190 patients undergoing operative laparoscopy for other adnexal masses and to that of 43 patients undergoing laparotomy for dermoid cysts from 1992 to 1996. The cysts were aspirated to reduce spillage and removed via a laparoscopic bag inserted in a 10-mm trocar. Culdotomy was never used. The abdominal cavity was abundantly flushed during the procedure and before closure. RESULTS: Dermoid cystectomy was successfully performed laparoscopically in 47 of 49 cases. Spillage occurred in 43 cases (88%), and postoperative fever occurred in 3 (6.1%). No case of peritonitis was recorded. Significant differences between laparoscopy and laparotomy were observed in the rate of bilaterality (4% vs. 25%), spillage (88% vs. 9%) and mean hospital stay (37 vs. 83 hours). When laparoscopic excision of dermoid cysts and other masses was compared, we did not observe any significant difference in operative time or complication rates, apart from transient fever. CONCLUSION: Laparoscopy is safe and effective for dermoid cysts and allows shorter hospitalization than laparotomy. As observed for other benign cysts, laparoscopy should become the technique of choice for the removal of most, if not all, ovarian dermoid cysts.

Adult↗

Peritoneal fluid levels of immunoreactive corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) in healthy and endometriosic women.

Corticotropin-releasing factor (CRF) is a 41-amino acid neurohormone involved in the neuroendocrine response to stress, also playing a role in cell-mediated immune functions and in inflammation. In the light of recent evidence showing an association between endometriosis and altered cellular immunity factors, the present study investigates immunoreactive (ir) CRF in the peritoneal fluid of healthy women, and in patients with pelvic adhesions and endometriosis. In addition, peritoneal fluid concentrations of CRF-binding protein (CRF-BP), a 37-kDA protein of 322 amino acids able to modulate central and peripheral CRF functions, were evaluated. Peritoneal fluid samples (n = 35) were collected from healthy women (n = 12), from patients with intrapelvic adhesions (n = 8), and from women with endometriosis (n = 15). In the control group a specimen of blood was collected. Peritoneal fluid and plasma CRF levels were measured by a two-site immunoradiometric assay (IRMA), and CRF-BP levels were measured by a specific radioimmunoassay (RIA). CRF and CRF-BP levels in peritoneal fluid were lower than plasma values, and independent of the phase of the menstrual cycle: in particular, in healthy women there was no significant difference between peritoneal fluid and plasma CRF-BP levels during two phases of the menstrual cycle. Peritoneal fluid levels of CRF and CRF-BP were similar in healthy patients and women with pelvic adhesions or with endometriosis, and when patients with adhesions or with endometriosis were considered as single group, no difference in CRF and CRF-BP levels was noted in comparison to the control group. In patients with endometriosis, no significant differences in peritoneal fluid CRF or CRF-BP levels were recorded, although in patients with stage 2 and stage 3 of the disease peritoneal fluid CRF-BP levels were higher than in healthy patients or in those with a lower grade of the disease. These results suggest that the peritoneal concentration of these hormones may reflect the circulating levels: the absence of any significative variations in peritoneal fluid CRF levels according to the degree of the endometriosis, suggests a limited role of CRF in the immunological changes related to the disease

Adult↗

The effect of tamoxifen and transdermal 17beta-estradiol on cerebral arterial vessels: a randomized controlled study.

OBJECTIVES: Our objective was to study the effects of tamoxifen on cerebral arterial reactivity. STUDY DESIGN: We studied the reactivity of both the internal carotid artery and the middle cerebral artery during a 12-month period of administration of either oral tamoxifen or transdermal estradiol or no treatment. A total of 45 healthy postmenopausal women who had undergone hysterectomy were followed up. Patients were randomly allocated to treatment with either oral tamoxifen 20 mg/day or transdermal estradiol 50 microg/day or nothing (15 patients in each group). They all underwent Doppler examinations of the internal carotid artery and middle cerebral artery at the beginning of the study and after 2, 6, and 12 months of treatment. The pulsatility index was measured. RESULTS: In the women given transdermal estradiol the pulsatility index of both the internal carotid artery and the middle cerebral artery was significantly reduced compared with that in the controls. Tamoxifen did not induce variations of pulsatility index in either artery during all the study period. The difference between the effect of the two drugs on the pulsatility index of both arteries was highly significant. CONCLUSIONS: Our findings demonstrate that tamoxifen does not cause any variation in the pulsatility index of cerebral arteries. The action of transdermal estradiol on the pulsatility index of cerebral arteries in postmenopausal women is the expression of a generalized action of estrogens on arterial vessels, and if this expression plays a role in the protective effect of hormone replacement therapy on risk of cardiovascular disease, tamoxifen treatment in healthy postmenopausal women should be considered with renewed caution.

Administration, Cutaneous↗

Soluble intercellular adhesion molecule-1 in ovarian follicles: production by granulosa luteal cells and levels in follicular fluid.

OBJECTIVE: To determine the concentration of the soluble form of intercellular adhesion molecule (ICAM)-1 in granulosa luteal cell-conditioned media and in follicular fluid (FF). DESIGN: Granulosa cells and FF samples were obtained at the time of oocyte retrieval for IVF. In 10 women, a total of 33 fluids were obtained from individual follicles, whereas in 70 women, the follicular aspirates were pooled. SETTING: Clinica "L. Mangiagalli" and Reproductive Center, San Raffaele Hospital, Milan, Italy. PATIENT(S): Eighty women referred for IVF for tubal factor or male factor infertility. INTERVENTION(S): Women underwent ovarian hyperstimulation. MAIN OUTCOME MEASURE(S): Soluble ICAM-1 was measured by an ELISA, and its levels were correlated with follicular size, the number of retrieved oocytes, and the number of follicles with a diameter of >15 mm. RESULT(S): The concentration of soluble ICAM-1 in granulosa luteal cell-conditioned media was 17.8 +/- 1.8 ng/5 x 10(5) cells. Interleukin-1beta can stimulate soluble ICAM-1 release in a dose-dependent manner. A significant positive correlation was demonstrated between levels of soluble ICAM-1 in pooled FF and the number of retrieved oocytes or the number of follicles with a diameter of >15 mm. CONCLUSION(S): Soluble ICAM-1 can be released by granulosa luteal cells and can be detected in FF after ovarian hyperstimulation. Levels of soluble ICAM-1 in FF correlate directly with some indices of ovarian function.

Cells, Cultured↗

Location and function of linker histones.

The linker histones, H1 and its variant forms, have been implicated in the formation of higher orders of chromatin structure and gene repression. Three recent manuscripts have reexamined the location of H1 within the nucleosome particle and its function in the regulation of transcription.

Animals↗

Surgical treatment of recurrent endometriosis: laparotomy versus laparoscopy.

The objective of this study was to clarify which is the better surgical conservative treatment for recurrent endometriosis. We compared two consecutive surgical series at a tertiary care centre for the cure of endometriosis. The patients were 81 women with recurrent endometriosis, 41 reoperated at laparotomy from 1986 to 1991 and 40 reoperated at laparoscopy from 1992 to 1996. Follow-up after the second operation included clinical and ultrasound examinations performed at least once a year to evaluate the recovery of fertility and the reappearance of symptoms and signs of the disease. The cumulative probability of recurrence of dysmenorrhoea (34 and 43 respectively), and the frequency of recurrence of pelvic pain and dyspareunia and of clinical findings suggestive of the disease were not significantly different in the two groups. The rate of recurrence of dyspareunia was higher in the patients operated at laparotomy as was the number requiring a third operation. However, this could be due to the longer follow-up of this group. No significant difference was observed between the cumulative pregnancy rates at 24 months in the two groups (45 in the laparotomy and 54 in the laparoscopy group). We conclude that operative laparoscopy seems as efficacious as conservative surgery at laparotomy in the treatment of recurrent endometriosis.

Adult↗

Expression of intercellular adhesion molecule (ICAM)-1 mRNA and protein is enhanced in endometriosis versus endometrial stromal cells in culture.

The relationship between the immune and the endometrial systems has been recently suggested to be critical to the development of endometriosis. We previously showed that one of the molecules involved in the complex events that allow this interaction is the adhesion molecule intercellular adhesion molecule (ICAM)-1. This study was designed to evaluate whether differences in ICAM-1 mRNA and protein expression might exist between eutopic endometrial cells and ectopic cells derived from endometriomas. Stromal cells were dispersed from samples of endometrium and ovarian endometriomas biopsied synchronously from 24 patients with endometriosis. We established that the relative expression of ICAM transcript was significantly higher in ectopic cells than that found in cultures derived from endometrial samples. Moreover, ectopic cells demonstrated a significant overexpression of ICAM-1 protein in both its cell-bound and soluble form (sICAM-1) (P < 0.05). Interestingly, endometrial secretion of sICAM-1 was shown to vary during the menstrual cycle as proliferative phase samples released significantly higher concentrations of the soluble protein compared to the secretory phase. In contrast, this cycle-dependent pattern was absent in stromal cells derived from endometriomas. Moreover, interleukin (IL-1beta) was able to increase sICAM-1 shedding from endometrial cells in a concentration-dependent manner and this IL-1beta-mediated induction could be slightly enhanced by oestradiol. As sICAM-1 is able to interfere with ICAM-1-mediated immune functions, the release of higher concentrations from ectopic samples may be the mechanism by which ectopic endometrial cells escape immunosurveillance.

Adult↗

Expression of intercellular adhesion molecule-1 messenger ribonucleic acid and protein in human term placental cells and its modulation by pro-inflammatory cytokines (interleukin-1beta and tumor necrosis factor alpha).

Intercellular adhesion molecule-1 (ICAM-1) is a ligand for the integrins lymphocyte function-associated antigen-1 (LFA-1) and complement receptor-3 (Mac-1), making it an important participant in many immune and inflammatory processes. Previous studies suggested that lack or reduced expression of ICAM-1 on trophoblast might partially explain its resistance to lysis by cytotoxic effectors. However, whether or not the adhesion molecule is expressed on placental cells is still a matter of debate. In this study, we determined ICAM-1 expression at mRNA, surface, and soluble protein levels on human trophoblasts throughout their functional differentiation in culture from cytotrophoblasts into syncytiotrophoblasts. Placental cells were obtained from 6 term placentas derived from normal pregnancies. ICAM-1 mRNA was detected by reverse transcription-polymerase chain reaction using two oligonucleotide primers specific for the human ICAM-1 gene. A single major DNA band of the expected size (943 base pairs) was obtained in both cytotrophoblasts and syncytiotrophoblasts. Flow cytometric analysis demonstrated expression of surface ICAM-1 protein on 45.5+/-3.5% of cytotrophoblasts. No changes were observed during differentiation in culture. Levels of the soluble form of ICAM-1 (sICAM-1) released by placental cells were undetectable when assessed by a specific ELISA. Finally, we investigated the effect of pro-inflammatory cytokines on placental ICAM-1 expression. Treatment of cultured trophoblasts for 24 h with interleukin-1beta (1 ng/ml) or tumor necrosis factor alpha (1 ng/ml) increased surface expression of ICAM-1 without inducing sICAM-1 shedding. However, on placental cells, the two cytokines exerted stimulatory effects lower than those detected on endometrial cells used as positive control. These observations document that the ICAM-1 gene is expressed in both cytotrophoblasts and syncytiotrophoblasts, suggesting that the molecule may be of value for some immune-mediated processes. On the other hand, the low sensitivity of trophoblasts to cytokine-mediated induction of ICAM-1 expression might represent a functional mechanism contributing to maternal tolerance for fetal graft.

Cell Differentiation↗