bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiologic Adaptations of Pregnancy
Authors: BRANCH D. WARE
Published: May 2013

ABSTRACT: Normal pregnancy changes include physiologic anemia, leukocytosis, and thrombocytopenia. Cardiac rate and stroke volume increase, vascular resistance falls, and creatinine clearance markedly rises. Thyroid binding globulin and Cortisol binding globulin both increase, as do complement proteins and fibrinogen, the latter resulting in a normally high erythrocyte sedimentation rate. Estrogen and progesterone rise dramatically. Low back pain, hip and sacroiliac complaints are common. The cytolytic activity of natural killer (NK) cells is decreased, as are adhesion and chemotaxis of phagocytic cells. Antibody responses are normal. CD4 cells proportionately decrease. A large number of circulating proteins suppression lymphocyte proliferation, and T‐cell interleukin‐2 (IL‐2) production may be suppressed. In studies of pregnant patients, controls must include normal pregnant women.
Immune Recognition at the Maternal‐Fetal Interface: Overview
Authors: MCINTYRE JOHN A.
Published: May 2013

ABSTRACT: Trophoblast antigens at the maternal‐fetal interface that are capable of stimulating maternal immune responses have been studied. Candidates are blood group I and P, HA, FcΔ‐receptors, TLX, and phospholipids. Antigens I and P on trophoblast have been implicated in pregnancy loss but incompatible i,p mothers are rare. HLA‐G is expressed on cytotrophoblast; however, no evidence for HLA‐G allotypy or maternal responses to these molecules exists, although HLA‐G has been implicated in recruitment of suppressor T cells. Receptors for IgG (FcΔ‐RI, FcΔ‐RII and FcΔ‐III) are present on trophoblast but allotypy is limited to the NA1‐NA2 antigen system associated with FcΔ‐RIII on neutrophils. Maternal Fc‐γR blocking antibodies have been linked to pregnancy success. The TLX alloantigen system was described by using xenogeneic antisera. Idiotype‐antiidiotype regulated maternal responses to TLX are proposed as necessary for successful pregnancy. Several putative TLX monoclonal antibodies (Mab) recognize a regulator of complement activation called MCP (membrane cofactor protein, or CD46). Mab to MCP do not exhibit allotypy. Syncytial and cytotrophoblastic membranes are rich sources of MCP. Preliminary data suggest that a conformational site induced by C3b (iC3) binding to MCP may be responsible for TLX allotypy. Certain pregnancy loss patients produce antiphospholipid antibodies (aPA). Some investigators believe that aPA recognize a plasma protein cofactor, β2GPI and not phospholipid per se. We produced three Mab specific for β2GPI, one of which fails to recognize β2GPI bound to phospholipid. By using these Mab in immunocytochemical studies of normal term placentae, β2GPI was observed on syncytial and cytotrophoblast as well as on fetal stem vessel endothelia. These Mab indicate that the β2GPI present in placentae is phospholipid bound.
The Effects of Sex Hormones on the Immune System in Pregnancy
Authors: LAHITA ROBERT G.
Published: May 2013

ABSTRACT: The immune system is affected by sex steroids. Immunoglobulin synthesis, T‐cell subsets, and a variety of cytokines are targets for sex steroids. Hormonal variations are found in patients with rheumatic diseases. These variations include the hydroxylation of estrone and the oxidation of testosterone, both of which are altered in rheumatic disease. These changes are magnified in the pregnant state. More estrogen metabolites of the C‐16 variety can bind to cells (lymphocytes and erythrocytes) and his reaction is accelerated in pregnancy. The role of the catechol estrogens is discussed. These compounds may be important to some of the vasospastic symptoms seen during pregnancy in patients; moreover, oxidation of testosterone to weak androgens is found in women with systemic lupus erythematosus (SLE). Overall, interesting observations and conclusions will evolve from a better undertanding of sex hormone metabolism and its effects on the immune system in pregnancy.
Condition Specific Antepartum Testing: Systemic Lupus Erythematosus and Associated Serologic Abnormalities
Authors: ADAMS DIANA , DRUZIN MAURICE L. , EDERSHEIM TERRI , BOND ANNETTE , KOGUT ELIZABETH
Published: May 2013

ABSTRACT: Antepartum fetal surveillance is well established in the optimal management of any pregnancy complicated by maternal systemic lupus erythematosus and/or its associated serologic abnormalities. Our experience in antepartum surveillance of the “lupus pregnancy” from 1980 to 1988 is reviewed. An overall perinatal mortality rate of 6.06% compares favorably to the total intrauterine death rate range usually reported for this disease.
Fetal Echocardiography in the Assessment of Lupus Pregnancies
Authors: FRIEDMAN DEBORAH M.
Published: May 2013

ABSTRACT: Fetal echocardiography is the most sensitive tool in detecting the earliest possible changes of the cardiovascular system related to maternal lupus. The institution of aggressive therapy at that time may still be able to reverse the process before permanent fetal cardiac injury occurs. Experience with this technique is described.
Early Doppler Studies in Lupus Pregnancy
Authors: KERSLAKE SIAN , MORTON KAREN E. , VERSI EBOO , BUCHANAN NEIL M. M. , KHAMASHTA MUNTHER , BAGULEY ELAINE , BRAUDE PETER , HUGHES GRAHAM R. V.
Published: May 2013

ABSTRACT: The management of 56 pregnancies in 54 patients is presented, 52 with systemic lupus erythematosus and two patients with primary antiphospholipid syndrome. All underwent serial Doppler blood flow studies of the umbilical and uterine arteries from 14 weeks of gestation. Drug therapy was directed at disease activity and the fetus and mother monitored intensively to identify optimum time for delivery. End diastolic blood flow (EDF) studies were compared with anticardiolipin antibodies (aCL) and the lupus anticoagulant (LAC) to predict outcome of pregnancy in terms of mortality, Caesarian delivery, hypertension, and gestation. The absence of end‐diastolic blood flow predicted Caesarian delivery more accurately. The presence of EDF and the absence of aCL was consistent with a normotensive pregnancy. The presence of LAC was the best of the three in predicting fetal demise.
Vascular Events in Placentae and Organ Allografts
Authors: FAULK W. PAGE , LABARRERE CARLOS A.
Published: May 2013

ABSTRACT: This investigation explores the transplantation analogy of placentae with allografted human organs. Biopsies of cardiac and renal allografts and placentae were studied immunocyto‐chemically with antibodies to components of the immunological, coagulational, anticoagulational, and fibrinolytic systems. Cellular rejection of cardiac and renal allografts was identified by infiltrating lymphocytes and macrophages. This was accompanied by vascular damage characterized by loss of endothelial anticoagulant pathways, vascular deposits of fibrin, and depletion of arterial tissue plasminogen activator (tPA). Failing allografts, including placentae from abnormal pregnancies, demonstrated coagulation/fibrinolytic changes consistent with vascular rejection, regardless of the presence of cellular infiltrates. An IgM autoantibody to allogeneic endothelium was associated with vascular protection. Its presence in cardiac and renal transplant biopsies was associated with an absence of fibrin deposits, and its absence was associated with vascular damage. Atherosclerosis commonly was identified in allograft biopsies (including placentae from abnormal pregnancies). These changes were shown in serial biopsies of transplanted hearts to be preceded by or associated with diminished IgM autoantibody, impaired endothelial anticoagulant pathways, vascular fibrin deposits, and depleted arterial reactivity for tPA. These results indicate the transplantation analogy of pregnancy should be viewed more specifically as vascular smooth muscle cell and endothelial responses to as yet unidentified microenvironmental stimuli.
A Study of 100 High Risk Lupus Pregnancies
Authors: BUCHANAN N.M.M. , KHAMASHTA M.A. , MORTON K.E. , KERSLAKE S. , BAGULEY E.A. , HUGHES G.R.V.
Published: May 2013

ABSTRACT: Certain subgroups of lupus patients and those with circulating antiphospholipid antibodies (aPL) in particular, suffer a high rate of fetal loss. Over the past 4 years, we have prospectively studied 100 pregnancies in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome. In addition to conventional methods of monitoring SLE and fetal development, we have also used Doppler flow assessment of placental perfusion from the 14th wk of pregnancy onward. Patients with the antiphospholipid syndrome and previous history of thrombotic events were treated with daily heparin (10,000 IU) and low‐dose aspirin (75 mg). Those without a history of thrombosis were treated with low‐dose prednisolone, azathioprine, or hydroxychloroquine. Pregnancy loss was reduced from 81.3% in 101 previous pregnancies to 36.8% in 100 pregnancies managed by us. None of the patients who received hydroxychloroquine throughout the pregnancy presented fetal malformations. Careful management and close monitoring of the lupus pregnancy has substantially improved fetal outcome.
Pregnancy and Rheumatoid Arthritis: An Overview
Authors: SPECTOR TIM D. , DA SILVA J.A.P.
Published: May 2013

ABSTRACT: The literature concerning the relationship of rheumatoid arthritis (RA) to pregnancy is reviewed. The amelioration of RA during pregnancy is a complex process. No specific factor that causes amelioration and is amenable to therapeutic intervention has been identified. Either RA is associated with lower fertility/fecundity, or pregnancy induces a protective effect against the development of the disease. The biological mechanism of these findings is not established.
Remission of Rheumatoid Arthritis During Pregnancy and Maternal‐Fetal Class II Alloantigen Disparity
Authors: NELSON J. LEE , HUGHES KATHLEEN A. , SMITH ANAJANE G. , NISPEROS BRENDA B. , BRANCHAUD ANN M. , HANSEN JOHN A.
Published: May 2013

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disorder known to be associated with specific class II genes. Although it has been known since 1938 that the majority of women with RA experience disease improvement or remission during pregnancy, the reasons remain unknown. Pregnancy represents an immunologic challenge and maternal immune recognition of the semi‐allogeneic fetus occurs as part of normal pregnancy. We hypothesized that maternal immune response to fetal HLA antigens might be associated with the effect of pregnancy on arthritis activity. To test this hypothesis, we studied HLA antigens in mother‐child pairs comparing maternal‐fetal HLA antigen sharing for pregnancies where arthritis improved with those where disease was active. No significant difference was observed in the two groups for class I HLA antigens. Fetal‐maternal disparity for HLA‐DR and HLA‐DQ antigens was observed significantly more frequently in pregnancies with remission or improvement compared with those in which disease was active. These observations suggest that maternal immune response to fetal paternally‐inherited class II HLA antigens may be important in RA remission observed during pregnancy.
Parity Status and the Development of Rheumatoid Arthritis
Authors: SILMAN ALAN J.
Published: May 2013

ABSTRACT: Rheumatoid arthritis (RA) is one of a number of autoimmune diseases with a marked female excess in incidence, particularly during the reproductive years. It is of interest to investigate whether reproductive factors are important in determining susceptibility to RA. However, difficulties in dating the pathological onset of the disease can make it difficult to distinguish between the reproductive influence history on disease and the influence of (subclinical) disease on reproduction.

In women with RA compared to controls, there is no excess of being unmarried. Most but not all studies, show an increase in nulliparity, whereas parity rates in fertile RA women are unchanged. There is an increased rate of onset postpartum, particularly in the first three months after delivery. There is no unifying biological explanation for these epidemiological findings, and it is likely that the apparently obvious link between reproductive experience and pregnancy is complex.
Colchicine Treatment in Conception and Pregnancy: Two Hundred Thirty‐one Pregnancies in Patients With Familial Mediterranean Fever
Authors: RABINOVITCH OSVALDO , ZEMER DEBORAH , KUKIA EHUD , SOHAR EZRA , MASHIACH SHLOMO
Published: May 2013

ABSTRACT: The effect of maternal use of colchicine on fetuses is unknown. The children of 116 women with Familial Mediterranean Fever (225 completed pregnancies) were studied. There was no unusual frequency of fetal abnormality among women taking colchicine before or during pregnancy. Colchicine treatment does not apparently harm mother or child.
Nocturnal Low Back Pain in Pregnancy: Polysomnographic Correlates
Authors: FAST AVITAL , HERTZ GILA
Published: May 2013

ABSTRACT: Thirteen women in late stages of pregnancy underwent a polysomnographic study. Eight women (61%) complained of mild nocturnal back pain or back discomfort. Five women (39%) did not complain of nocturnal back pain. The two groups did not differ in total bed time, total sleep time, sleep latency, and wake after sleep onset (WASO). A significant decrease in rapid eye movement (REM) sleep and an increase in stage 2 were observed in the pain group. The same group had a statistically significant decrease in the basal O2 saturation level. The pain group also spent a longer time sleeping in the supine position. We hypothesize that a prolonged stay in the supine position leads to obstruction of the vena cava. In the presence of inadequate collateral circulation, increased pressure and venostasis in combination with a decrease in basal oxygen saturation may lead to hypoxemia, compromise the metabolic supply of the neural structures, and result in pain. It appears, therefore, that the vascular system plays an important role in the pathogenesis of pain. The role played by the disturbed sleep architecture in the production of pain remains to be established. It is possible that the changes observed in sleep architecture result from pain rather than contribute to pain production;.
Neonatal Lupus Erythematosus in Offspring of Mothers With Experimental Systemic Lupus Erythematosus
Authors: KALUSH FRANCIS , RIMON EPHRAIM , MOZES EDNA
Published: May 2013

ABSTRACT: Neonatal lupus erythematosus (NLE) syndrome is a result of the transfer of autoantibodies produced by the mother, across the placenta, to the fetus. NLE is characterized by a transient dermatitis, a variety of systemic and hematological abnormalities, and isolated cases of congenital heart block. The latter has been reported to be due to the presence of autoantibodies specific to La (SS‐B) and/or Ro (SS‐A). As female mice with experimental SLE, induced by immunization with the monoclonal anti‐DNA 16/6 Id, produce a variety of autoantibodies including anti‐Ro and anti‐La antibodies, we examined the relevance of NLE in the murine system. Offspring of SLE‐afflicted BALB/c mothers possessed antibody titers to the 16/6 Id, ssDNA, and nuclear extract, which gradually declined until reduced to normal levels by day 60 after delivery. Antibody titers in the sera of the mothers remained elevated throughout this period. Electrocardiograms were recorded from groups of neonates from mothers with experimental SLE. The results indicated that a high percentage of the offspring had defects in their conduction system including first, second, and third degree heart block; significant bradycardia; and wide QRS complex. Normal patterns were observed in offspring of healthy mothers. Experiments done with mice that were exposed to SLE‐related autoantibodies early in their development indicated that offspring to mothers with experimental SLE were neither protected nor more susceptible to disease induction by the 16/6 Id.
Immune Features in Complete Freund Adjuvant‐Treated CBA/J Mouse Model
Authors: STRASSBURGER D. , IRLIN Y. , CARP H. , LURIE S. , PECHT M. , TRAININ N. , TODER V.
Published: May 2013

ABSTRACT: Immunostimulation with complete Freund adjuvant (CFA) reverses the tendency to fetal loss in the CBA/J × DBA/2J mouse. First attempts to understand the mechanisms underlying this effect were to evaluate phenotypic and functional changes in the lymphocytic cell population after immunopotentiation. We demonstrated that treatment with CFA leads to diminished responses of maternal splenocytes towards paternal alloantigens and this low response cannot be improved with exogenous interleukin‐2. Lymphocytes derived from spleen, paraaortic draining lymph nodes and placenta significantly suppress maternal response to paternal antigens. The effect of low fetal resorption rate is followed by marked elevation of asialo GM‐1 and HNK‐1‐positive cells but not followed by any change of the L3T4 or Lyt‐2‐positive lymphocyte population in either the spleen or in draining lymph nodes. L3T4 and Lyt‐2‐positive cells have not been found in the placenta. An important feature was marked elevation of Mac‐1‐positive cells in the placentas of CFA‐treated animals. The relevance of these findings to CFA‐induced fetal protection is still under investigation.
Comparison of the Proportions of Leukocytes in Early and Term Human Decidua
Authors: VARGAS MARIA LUISA , SÅNTOS JUAN L. , RUIZ CONCEPCIÓN , MONTES MARIA JOSÉ , ALEMÁN PILAR , GARCÍA‐TORTOSA CARMEN , GARCÍA‐OLIVARES ENRIQUE
Published: May 2013

The percentages of cells expressing immune markers were determined with immunohistochemistry and flow cytometry in early and term human decidua. Although we found no variation in the proportion of cells of bone marrow origin (CD45 +), the percentages of T cells and CD 16 + lymphocytes were significantly higher in term decidua. On the contrary, CD56+ lymphocytes, the most abundant leukocyte type in early decidua, decreased at term. These variations may reflex the immunological adaptations of decidua during pregnancy.
Stress‐Triggered Abortion in Mice Prevented by Alloimmunization
Authors: CLARK DAVID A. , BANWATT DALJEET , CHAOUAT GERARD
Published: May 2013

PROBLEM: To determine if immunotherapy can prevent abortion triggered by mechanisms that in humans may be treatable by psychotherapy.

METHOD: The effects of alloimmunization against paternal strain antigens were tested in pregnant mice subjected to stress.

RESULTS: Restraint stress boosted the resorption rate assessed on day 13.5 of pregnancy in DBA/2‐mated C3H/HeJ mice with an optimal effect on day 4.5 of pregnancy, and premating alloimmunization greatly reduced the effect. By contrast, CBA/J and A/J mice proved resistant to abortion boosting by restraint stress. A/J mice mated to DBA/2 or C3H/HeJ males showed reduced fertility, perhaps due to failure of pregnancy immediately after the stress, but this was not corrected by alloimmunization with either DBA/2 [class I + class II major histocompatibility complex (MHC) immunogen] or C3H/HeJ (class I MHC immunogen) splenocytes. There was a reduction in the endogenous resorption rate, however, and implantation number was slightly increased by preimmunization using DBA/2 cells. The abortion rate could be boosted, however, by ultrasonic noise stress of high abortion rate CBA/J, and preimmunization using BALB/c (H‐2d) splenocytes protected. A similar boosting of loss in low abortion rate BALB/k mice was ameliorated (albeit not completely) by preimmunization with allogeneic paternal but not syngeneic splenocytes.

CONCLUSIONS: Immunotherapy may protect against a variety of potential triggers of spontaneous abortion, including those that may be amenable to psychological remedies, and possible mechanisms are discussed.
A Set of MHC Haplotypes Found Among Finnish Couples Suffering From Recurrent Spontaneous Abortions
Authors: LAITINEN TARJA
Published: May 2013

PROBLEM AND METHOD: The role of major histocompatibility complex (MHC) genes in the etiology of recurrent spontaneous abortion (RSA) was studied by analyzing the polymorphism of several, at least 14, immunogenetically important MHC genes either by serological or molecular methods in 56 Finnish RSA couples, and in 29 infants born to these families during the follow‐up period of two years after the abortions.

RESULTS: The haplotype analysis showed that the RSA couples had significantly increased sharing of MHC fragments, compared to the control families. Furthermore, the MHC risk markers for abortions defined 12 different, extended MHC haplotypes that were found in a significantly higher proportion among persons in the RSA group (45%) than in the controls (11%). However, neither of these observations associated with the reproductive success of the study couples.

CONCLUSIONS: The results suggest that extended MHC haplotypes, disadvantageous for reproduction, exist in some isolated populations, such as the Finns.
Predominant Production of Amniotic Interleukin‐1α in Cases With Premature Rupture of the Membranes
Authors: HIRANO KOHKI , DAITOH TOSHIFUMI , KAMADA MASAHARU , MAEDA NOBUHIKO , OHMOTO YASUKAZU , AONO TOSHIHIRO
Published: May 2013

PROBLEM: The physiological significances of the two known subtypes of interleukin‐1 (IL‐1) in amniotic fluid (AF) were examined by measurements of their concentrations and detection of their location.

METHOD: Each IL‐1 subtype in AF collected from 61 patients were examined by newly developed enzyme‐linked immunosorbent assay with high sensitivity. Placenta and umbilical cord from 17 patients were examined immunohistochemically for localization of IL‐1.

RESULTS: Different types of IL‐1 were predominant in AF; the mean (± SE) concentration of IL‐1β (412.8 ± 105.4pg/ml) was significantly higher (P<0.01) than that of IL‐1α(116.4± 26.7 pg/ml) in cases with spontaneous vaginal delivery, whereas the concentration of IL‐1α (243.1 ±81.4pg/ml) was significantly higher(P<0.01)than that of IL‐1β (139.7±59.4pg/ml) in cases with premature rupture of the membranes (PROM) without intrauterine infection. In these cases, immunohistochemical studies revealed the presence of IL‐1α in the trophoblastic layer of the placenta and epithelium of the umbilical cord.

CONCLUSIONS: Amniotic IL‐1α was detected predominantly in cases with PROM, and it is thought to be produced in placenta and fetal skin keratinocyte.
Low Periconceptional Maternal Serum Thymosin α1 Levels Are Associated With Blighted Pregnancies
Authors: KAUFMANN ROBERT A. , WELCH ROBERT A. , MUTCHNICK MILTON G.
Published: May 2013

OBJECTIVE: The thymus‐derived peptides, thymosin α1 and thymosin (β4, are believed to contribute to the maintenance of immune homeostasis. They are also associated with the hypothalamic‐pituitary‐adrenal‐gonadal axis and may play a role in reproduction. STUDY DESIGN: Patients were recruited from a university hospital setting. Eligible candidates were 24 to 38 years old who were being seen in an ovulation induction and in vitro fertilization program. Serial maternal serum thymosin α1 and β4 levels were assayed preconceptual and then twice in the first trimester by ELISA in 28 women with known ovulation dates who successfully conceived as demonstrated by positive serum β human chorionic gonadotropin (hCG). Thymosin α1 and β4 serum levels for viable pregnancies (group I; N = 19) were compared to pregnancies that aborted (group II; N = 9) using repeated measures of multivariate analysis of variance (MANOVA). Periconceptional (preovulatory and early pregnancy) thymosin α1 and β4 values between groups I and II were compared using repeated measure one‐way ANOVA.

RESULTS: Thymosin α1 levels from pregnancies that remained viable were significantly higher than those from pregnancies that spontaneously aborted. Preovulation thymosin α1 levels also tended to be lower in pregnancies that subsequently aborted. Thymosin β4 levels were similar between the two groups.

CONCLUSIONS: Decreased maternal serum thymosin α1 levels may be associated with periconceptional endocrine and/or immune disturbances preceding miscarriage.
Interspecies‐specific Ovarian Autoantigens Involved in Neonatal Thymectomy‐induced Murine Autoimmune Oophoritis
Authors: XUN ZHU , MARUYAMA HIDENORI , UEDA MASAMICHI , FUKUMOTO MANABU , MASUDA TOHRU
Published: May 2013

PROBLEM: Thymectomy of mice on day 3 after birth (3d‐Tx) gives rise to the appearance of a particular type of ovarian lesion known as experimental autoimmune oophoritis (AIO).

METHOD: In the present study, the spleen cells from BALB/c mice having undergone 3 day‐Tx AIO were fused with X63‐Ag8‐6.5.3 myeloma cells, and a number of hybridoma clones producing autoantibodies against ovarian tissue were established.

RESULTS: On the basis of immunohistochemical and protein‐chemical analysis, two independent clones, designated as T2.2 and S1.6, were found to react with interstitial tissues surrounding the follicles. These monoclonal antibodies showed broad cross‐species reactivity, in that they recognized similar antigenic macromolecules in the rat, pig, human, and mouse. The antigenic determinants were strongly resistant to heat and acid, especially to the treatment of periodic acid, indicating that the antigenic determinants had no relation with carbohydrate components.

CONCLUSIONS: By antibody affinity chromotography, two kinds of autoantigens were identified. SDS‐PAGE, under reduced or nonreduced conditions, revealed an 80/85 kDa protein for T2.2, and an 82 kDa for S1.6, respectively.
Recurrent Spontaneous Abortion: Histocompatibility Between Partners, Response to Immune Therapy, and Subsequent Reproductive Performance
Authors: VAN IDDEKINGE B. , HOFMEYR G.J. , BEZWODA W.R. , WADEE A.A. , VAN ROOY P.
Published: May 2013

PROBLEM: Immunological factors may account for previously unexplained cases of recurrent abortion.

METHOD: After screening 76 couples for causes of recurrent spontaneous abortion and measuring maternal antipaternal immunity, 23 primary spontaneous recurrent aborters were immunized once with their husbands' leukocytes. Testing for antipaternal cytotoxicity was repeated in 21 couples. Seroconversion was significantly less frequent in couples who shared more than one human leukocyte antigen [one of five (20%) versus 13 of 16 (81%), P < .02].

RESULTS: Twelve of 16 women (75%) who became pregnant had live children and five of those have had a second live child. All 12 women who achieved successful pregnancies had become antipaternal cytotoxic antibody‐positive after immunization, whereas all four patients who had repeat abortions had failed to seroconvert (P < .001). However, this relationship is not necessarily causative, as the successful group also tended to have fewer previous abortions and less human lymphocyte antigen sharing.

CONCLUSION: Except for transient illness after immunization, one moderately small for gestational age baby and one premature labor at 32 wk, no complications were observed after immunization.
Endometrial Expression of mRNA Encoding Epidermal Growth Factor Receptor in Normal and Leiomyomatous Uteri Throughout the Menstrual Cycle
Authors: HEINER JAMES S. , WANG L. , RUTGERS J.K.L. , WAN Y.‐J.Y. , CAI L. , WU T.‐C.J.
Published: May 2013

PROBLEM: To investigate the relationship between the histologic phase and the quantitative expression of epidermal growth factor receptor (EGFR) mRNA in the endometrium of normal and leiomyomatous uteri.

METHODS: To test this relationship, endometrium was collected at hysterectomy from 38 women with a history of regular cycles. Total RNA (20 μg) was isolated and analyzed by Northern blot using a human EGFR‐specific 32P labeled cDNA probe. The hybridization signals were quantified by densitometry, standardized, and reported in densitometry signal units. Separate portions of the same endometrial specimens were simultaneously prepared for histologic evaluation. The differences between menstrual phases were evaluated by Student's t‐test.

RESULTS: EGFR mRNA was expressed in all endometrial tissues tested. Levels were higher in the midproliferative phase than in all other phases for both myomatous and nonmyomatous uteri (P <.05). Myomatous uteri showed lower expression than nonmyomatous uteri in the early and late proliferative phase (P <.05). Age did not appear to alter endometrial EGFR mRNA expression.

CONCLUSION: This data suggest that endometrial EGFR mRNA expression varies in association with the histologic changes of the normal menstrual cycle, and may be associated with the presence of leiomyomata uteri.
Immunocytochemical Localization of Transforming Growth Factor‐α and Epidermal Growth Factor Receptor in Human Fallopian Tubes and Cumulus Cells
Authors: EL‐DANASOURI I. , FRANCES A. , WESTPHAL L.M.
Published: May 2013

PROBLEM: Transforming growth factor‐a (TGF‐α) has been shown to be a potent stimulant of oocyte maturation and embryonic development. The role of maternal growth factors and their mechanism of action in early mammalian development is not well understood.

METHOD: In this study, the presence of TGF‐α and epidermal growth factor receptor (EGF‐R) in human cumulus cells and fallopian tubes was investigated by immunocytochemical techniques.

RESULTS: The fallopian tube showed intense staining for TGF‐α in the apical region of the epithelial cells, and the cumulus cells showed intense staining for EGF‐R on cell membranes.

CONCLUSION: The presence of TGF‐α in the fallopian tube epithelium and its receptor on cumulus cells suggest a paracrine mechanism between maternal growth factors and the developing embryo.
Absence of Immunoreactive Cytokines in Supernatants of Individual Preimplantation Human Embryos
Authors: SEIFER DAVID B. , ROMERO ROBERTO , BERLINSKY DAVID , HANING RAY V.
Published: May 2013

PROBLEM: The purpose of this study was to determine if it was possible to use commercially available enzyme‐linked immunosorbent assay (ELISA) kits to quantitate specific cytokine production from individual embryos.

METHODS: We examined the supernatants of individual two to six cell preimplantation human embryos using commerically available kits for IL‐1 alpha, IL‐1 beta, IL‐6, and LIF.

RESULTS: Cytokines were undetectable in all media samples analyzed.

CONCLUSION: While it is possible that individual preimplantation embryos may produce cytokines, we believe these concentrations are below the detectable limits of the commercial assays used in this study.
Antisperm Antibody Binding to Human Sperm Inhibits Capacitation Induced Changes in the Levels of Plasma Membrane Sterols
Authors: BENOFF SUSAN , COOPER GEORGE W. , HURLEY IAN , MANDEL FRANCINE S. , ROSENFELD DAVID L.
Published: May 2013

PROBLEM: Human spermatozoa express mannose ligand receptors (MLRs) over the entire head when incubated under conditions that promote loss of free cholesterol. Binding of IgA, IgG. and/or IgM head‐directed anti‐sperm antibodies (ASAs) to freshly isolated sperm blocks MLR expression in a dose dependent manner.

METHODS: Comparison of Western blots of immunoprecipated glycoproteins from fresh sperm exposed to ASAs from women with those of sperm membrane proteins isolated from capacitated sperm probed with a goat anti‐human macrophage MLR antiserum showed that ASAs do not react with human sperm MLRs of 48 and 61 kd apparent molecular weight.

RESULTS: The direct effect of ASA binding was to increase membrane free cholesterol content which remained greater than 0.005 μmol/109 sperm after 18 h incubations, whereas the sterol content of controls decreased to less than 0.001 μmol/109 sperm. Cholesterol addition to sperm inhibited MLR expression in a manner analogous to ASA binding, while increasing temperatures up to the crystalline/liquid‐crystalline phase transition for sperm membranes; less than 45°C failed to promote the appearance of MLRs on the surface of fresh sperm.

CONCLUSIONS: We conclude that ASA effects on membrane cholesterol content prevent the membrane fluidity changes needed for MLR expression.
Differential mRNA Expression and Production of Interleukin‐6 in Placental Trophoblast and Villous Core Compartments
Authors: KAUMA S.W. , HERMAN K. , WANG Y. , WALSH S.W.
Published: May 2013

PROBLEM: Interleukin‐6 (IL‐6) is a plieotrophic protein that functions as an immunoregulatory peptide, growth factor, and endocrine hormone. IL‐6 has been shown to be produced in whole placental tissue and isolated trophoblast (TC). In addition, the villous core (VC) compartment of the placenta contains cell types (fibroblasts, macrophages) capable of IL‐6 production. Consequently, the present study was designed to determine the relative contribution of the TC and VC compartments to placental IL‐6 production.

METHOD: The VC and TC compartments from term pregnancies were separated using CR‐Dispase digestion and Percoll density gradient centrifugation. The VC, TC, and whole placental tissues were cultured in Dulbecco's modified Eagle's medium over a 28‐h period. Relative IL‐6 mRNA expression was determined by dot blot analysis and secreted IL‐6 protein was determined by enzyme‐linked immunosorbent assays.

RESULTS: All three tissues demonstrated linear production of IL‐6 protein over the culture period. At 28 h, whole placental tissue produced the most IL‐6 (5.1 ng ± 0.8 ng/μg protein) followed by TC (4.0 ng ± 1.3 ng/μg) and VC (0.55 ng ± 0.24 ng/μg). Although production rates of IL‐6 were 8.4‐fold higher in TC compared to VC (P<.05), steady‐state IL‐6 mRNA expression was 3.5‐fold higher in freshly isolated VC compared to TC (P<.0001) and 13‐fold higher in VC compared to TC (P<.01) after 24 h in culture.

CONCLUSIONS: These results demonstrate that: (1) the placenta can produce large quantities of immunoreactive IL‐6 in vitro, (2) TC produce significantly more IL‐6 than VC although both compartments contribute to placental IL‐6 production, (3) placental IL‐6 production and secretion are probably posttranscriptionally regulated since steady‐state IL‐6 mRNA expression in VC and TC compartments did not correlate with IL‐6 production.
Ultrastructural Localization of Insulin Receptors in Human Placenta
Authors: JONES CAROLYN J.P. , HARTMANN MICHAELE , BLASCHITZ ASTRID , DESOYE GERNOT
Published: May 2013

PROBLEM: Investigations to date on localization of placental insulin receptors (IR) at the ultrastructural level focused on the maternal facing side of the placenta but did not allow localization of IRs to intracellular compartments.

METHOD: The ultrastructural localization of IR in placentae from early and term gestation was studied using the immunogold technique and a monoclonal antibody against the external domain of the IR (clone MA20).

RESULTS: At 10 wk gestation, there were high levels of IR in both cytotrophoblast and syncytiotrophoblast, with sparse microvillous labeling. Fetal vessels contained various amounts of IR while stromal cells were also labeled. By 13 wk, this pattern was unchanged; however, at term, fewer IR were present in the syncytiotrophoblast, with more label on microvilli than before. Fetal vessels were well labeled, while stromal cells appeared unchanged. Intense labeling of fetal erythrocytes provided an internal positive control, while omission of the primary antiserum produced loss of binding.

CONCLUSION: The data suggest a spatiotemporal alteration in placental IR distribution during pregnancy, possibly reflecting a shift in control of placental growth and metabolism from mother to fetus.
Evidence for a Common Mechanism of Action of Interleukin‐1β, Tumor Necrosis Factor‐α, and Epidermal Growth Factor on Prostaglandin Production in Human Chorion Cells
Authors: POLLARD J.K. , THAI D. , MITCHELL M.D.
Published: May 2013

PROBLEM: Although chorion produces prostaglandins in response to interleukin‐1β (IL‐1β), tumor necrosis factor alpha (TNFβ), and epidermal growth factor (EGF), little attention has been given to the mechanisms of action of prostaglandin biosynthesis in this tissue.

METHODS: IL‐1β, TNFβ, and EGF induced a concentration‐related stimulation of prostaglandin E2 (PGE2) biosynthesis in human chorion cells, and this stimulation was enhanced by the addition of exogenous arachidonic acid.

RESULTS: Protein synthesis inhibition with cycloheximide or actinomycin D resulted in complete abrogation of the stimulation of PGE2 production by IL‐1β, TNFα, and EGF. Finally, all three stimulants induced a more rapid recovery of PGE2 production in chorion cells after ace‐tylsalicylic acid pretreatment than controls.

CONCLUSIONS: It is suggested that IL‐1β, TNFα, and EGF all act to stimulate human chorion PGE2 production primarily via induction of prostaglandin endoperoxide synthase activity.
Cyclosporin A Attenuates Increased Prostaglandin and Thromboxane Production in Response to Various Stimuli in Human Decidua
Authors: EDWIN S.S. , BRANCH D.W. , SCOTT J.R. , SILVER R.M. , MITCHELL M.D.
Published: May 2013

PROBLEM: This study was undertaken to evaluate the effects of cyclosporin A on prostanoid (prostaglandin and thromboxane) production by human decidua.

METHOD: Decidual cells were isolated from term placentae obtained at elective cesarean section before the onset of labor. Cells were grown to confluence and then incubated for 16 h with cyclosporin A (0.1–100 ng/ml) in the presence and absence of interleukin 1β (IL‐1β, 10 ng/ml), phorbol 12‐myristate 13‐acetate (PMA, 10−7M) and ionomycin (0.5 μm). Prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were measured by radioimmunoassay, and cellular protein was determined.

RESULTS: IL‐1β, PMA, and ionomycin all stimulated decidual PGE2 and TXB2 production as expected. However, these stimulatory actions were attenuated by 20% when cells were coincubated with cyclosporin A (100 ng/ml). All concentrations of cyclosporin A tested were within the therapeutic range.

CONCLUSIONS: Our results indicate that cyclosporin A does not stimulate decidual prostanoid production and is probably unrelated to preterm labor and delivery in allograft recipients.
Evidence of Participation of the Soluble Tumor Necrosis Factor Receptor I in the Host Response to Intrauterine Infection in Preterm Labor
Authors: BAUMANN PETER , ROMERO ROBERTO , BERRY STANLEY , GOMEZ RICARDO , MCFARLIN BARBARA , ARANEDA HERIBERTO , COTTON DAVID B. , FIDEL PAUL
Published: May 2013

PROBLEM: This study was conducted to determine whether: (1) the soluble tumor necrosis factor receptor I (sTNF‐r I) is present in human amniotic fluid, neonatal urine, and the feto‐maternal plasma; (2) there are changes in the concentration of the sTNF‐r I in amniotic fluid with gestational age; and (3) microbial invasion of the amniotic cavity (in term and preterm parturition) is associated with changes in amniotic fluid sTNF‐r I concentrations.

METHOD: Amniotic fluid was retrieved by amniocentesis from 185 women classified into 11 groups according to gestational age (midtrimester, preterm gestation, and term), the presence or absence of labor, spontaneous rupture of membranes and microbial invasion of the amniotic cavity. sTNF‐r I was assayed with a sensitive and enzyme‐linked immunosorbent assay (ELISA) validated for amniotic fluid. In addition, sTNF‐r I concentrations were determined in fetal blood obtained by cordocentesis in preterm gestations (N = 24) or at the time of delivery after spontaneous labor at term (N = 10). sTNF‐r I concentrations were also measured in maternal venous and cord blood and neonatal urine (n = 13).

RESULTS: sTNF‐r I was found to be present in all amniotic fluid samples, maternal blood and fetal blood and neonatal urine samples; sTNF‐r I concentrations were higher in the midtrimester than at term (mean ± SD:36.2 ± 12.2 ng/ml versus mean ± SD:5.56 ± 5.72ng/ml [P < .05]); patients with preterm labor and microbial invasion of the amniotic cavity (with intact or with ruptured membranes) had significantly higher amniotic fluid concentrations of sTNF‐r I than patients without microbial invasion; in the absence of microbial invasion, parturition (both term and preterm) was not associated with changes in amniotic fluid concentrations of sTNF‐r I; neonatal urine contained the highest concentrations of sTNF‐r I of all biological fluids assayed including maternal and neonatal/fetal blood and amniotic fluid.

CONCLUSIONS: It was concluded that sTNF‐r I is a physiologic constitutent of amniotic fluid, as well as of the fetal and maternal plasma; that amniotic fluid sTNF‐r I concentrations decrease as a function of gestional age and increases in the concentration of the sTNF‐r I are part of the host response to intrauterine infection in preterm parturition.
Dysfunction of Monocytes and Dendritic Cells in Patients With Premature Ovarian Failure
Authors: HOEK ANNEMIEKE , VAN KASTEREN YVONNE , DE HAAN‐MEULMAN MEENY , SCHOEMAKER JOOP , DREXHAGE HEMMO A.
Published: May 2013

PROBLEM: Due to the presence of ovarian antibodies it has been suggested that premature ovarian failure (POF) belongs to the autoimmune endocrinopathies. Monocytes and the monocyte‐derived dendritic cells play a prominent role in the initial stages of endocrine autoimmune reactions: the accumulation of monocytes/dendritic cells and the clustering of dendritic cells in endocrine organs is one of the first phenomena of an autoimmune endocrinopathy.

METHOD: This report describes a study on (1) the chemotactic responsiveness of blood monocytes, and (2) the cluster capability of blood dendritic cells in POF patients. The monocyte chemotaxis was determined using the cell's capability to polarize (changes in shape determined by light microscopy) under the influence of the chemoattractant, N‐formyl‐methionylleucyl‐phenylalanine (fMLP). The cluster capability of dendritic cells was tested by allowing the dendritic cells to form aggregates with allogenic lymphocytes in vitro.

RESULTS: The blood monocytes of 46% of a total of 28 POF patients showed a decreased fMLP induced monocyte polarization in comparison to healthy control values. None of the young female controls (N = 28) and postmenopausal women (N= 17), showed such a defective monocyte polarization. The blood dendritic cells of 36% of the POF patients showed a decreased cluster capability. Defects in monocyte polarization and dendritic cell clustering were not affected by therapies aimed at changes in the estrogen levels or gonadotropin levels of the patients [using estrogen substitution therapy, gonadotropin‐releasing hormone (GnRH) analog, follicle‐stimulating hormone (FSH)].

CONCLUSIONS: A redistribution of active monocytes and of active dendritic cells from the peripheral blood to the ovaries may be the cause of the described abnormalities. Since similar abnormalities in monocyte function and dendritic cell function have been described in Graves' disease and type I diabetes, the data strengthen the view that POF is one of the endocrine autoimmune diseases.
Differences Between Human Sperm and Somatic Cell DNA in CpG Methylation Within the HLA Class I Chromosomal Region
Authors: GUILLAUDEUX THIERRY , D'ALMEIDA MARTA , GIRR MARYSE , RODRIGUEZ ANNE‐MARIE , PONTAROTTI PIERRE , FAUCHET RENEE , BOUTEILLER PHILIPPE LE
Published: May 2013

PROBLEM: We investigated the possible negative regulatory mechanisms that repress classical human leukocyte antigen (HLA) class I gene expression in human spermatozoa and searched for novel testis‐specific coding sequences that might be present in the MHC class I chromosomal region.

METHOD: We performed a comparative DNA methylation analysis of this genomic region in both purified human spermatozoa and mononuclear blood cells from the same donors, using methylation‐sensitive restriction enzymes followed by classical or pulsed field gel electrophoresis and hybridization with HLA class I locus‐specific probes.

RESULTS: Unmethylated CpG sites were detected in the 3′ part of HpaII tiny fragments of the HLA‐F and HLA‐G genes in spermatozoal DNA. In contrast, no difference was observed in the methylation status of the HLA‐B, HLA‐C, and HLA‐E genes between germ and somatic cells. CpG unmethylation events were also detected in several parts of this chromosomal region (outside the known loci) in spermatozoal DNA.

CONCLUSIONS: These results suggest that this genomic region undergoes changes in its DNA methylation pattern during the developmental process. We hypothesize that these dynamic changes have functional importance, including a possible transcriptional activity of nonclassical class I genes and/or as yet undescribed testis‐specific coding sequences.
Immunoneutralization of Heterodimeric FSH Using FSH Beta Subunit as the Immunogen
Authors: BUTTERSTEIN G.M. , SACHAR D. , DIAS J.A.
Published: May 2013

PROBLEM: Immunization with beta subunit of gonadotropin may elicit antibody formation to endogenous heterodimeric gonadotropin and result in reproductive unresponsiveness. The objectives of this study were to determine if antibodies produced in rats following immunization with human follicle stimulating hormone beta‐subunit (hFSH‐β) could bind to and immunoneutralize heterodimeric FSH, and to elucidate the immunoneutralizing epitope.

METHOD: Mature female Sprague‐Dawley rats received subcutaneous injections of 10 μg of hFSH‐β emulsified in complete Freund's adjuvant, while control animals received only adjuvant. Animals received 10 μg hFSH‐β booster injections emulsified in incomplete Freund's adjuvant 2,4, 11, and 21.5 wk after the initial immunization.

RESULTS: Immunization with hFSH‐β produced appreciable antibody titers against human FSH (hFSH) as measured in enzyme‐linked immunosorbant assays (ELISA) of immunized rat sera. A more modest titer to rat (rFSH) and no antibody response to rat Luteinizing Hormone (rLH) was observed, thus confirming the specificity of the immune response. Titers against hFSH increased throughout the study. Rat anti‐hFSH‐β sera was tested to determine its ability to inhibit binding (immunoneutralizing) of 125I‐hFSH to the FSH receptor. Continued immunization resulted in all animals producing immunoneutralizing antibodies. Immunization of rats also resulted in disrupted estrous cycles, but only animals with subsequent titers high enough to completely block binding of FSH to its receptor failed to conceive.

In order to assess the immunoneutralizing epitope, antisera were tested in a peptide ELISA. Peptides used in the ELISA corresponded to amino acids that spanned the entire hFSHB sequence. It was found that antibodies from all rats immunized with hFSHβ bound to amino acids within hFSH‐β 33–53.

CONCLUSIONS: Collectively, these data suggest that amino acids within hFSH‐β 33–53 are necessary but not sufficient to confer immunocontraception. Amino acids within this linear sequence appear in a variety of epitopes of hFSH‐β and hFSH, only some of which are immunoneutralizing.
Assessment of Circulating Agglutinating Anti‐Sperm Antibodies in Buffalo Cows With Unexplained Infertility and an Attempt to Identify Buffalo Sperm Isoantigens
Authors: KANCHEV LUBOMIR , PAVLOVA SOPHIA , DANEV ATANAS
Published: May 2013

The presence of circulating agglutinating anti‐sperm antibodies as cause for unexplained infertility of artificially inseminated buffalo cows was assessed. An attempt to identify buffalo sperm isoantigens was also made. The following methods were applied for that purpose: the tray agglutination test (TAT), SDS‐polyacrylamide gel electrophoresis, and immunoblotting. The results obtained showed that three of 90 sera from buffalo cows with unexplained infertility were positive in TAT (3.3%) and their titers were low. A total of 27 spermatozoal polypeptides reacted positively with the IgG‐isoantibodies of one of the sperm agglutinating sera in immunoblotting. Of the control sera 12 also revealed individual variations in the number of positive fractions on the blots. On the basis of comparing the blot with the positive sperm agglutinating serum to the blots of the positive controls, two buffalo sperm isoantigens were identified, with the respective molecular weights of 40 kDa and 120kDa.

In conclusion, circulating agglutinating anti‐sperm antibodies are very rarely detected in buffalo cows with unexplained infertility after several artificial inseminations.