bluuebunny/crossref_metadata_2025 huggingface dataset:
Sera From Preeclamptic Women Specifically Activate Human Umbilical Vein Endothelial Cells In Vitro: Morphological and Biochemical Evidence
Authors: ROBERTS JAMES M. , EDEP MARTIN E. , GOLDFIEN ALAN , TAYLOR ROBERT N.
Published: May 2013

ABSTRACT: Endothelial cell dysfunction could explain many of the pathophysiological changes observed in preeclampsia. Markers of endothelial cell activation including increased circulating Von Willebrand factor (VWF) and cellular fibronectin (cFN) antedate clinically evident disease. We have therefore proposed that alteration of endothelial cell function by circulating agent(s) produced by the placenta initiates the clinical syndrome. This hypothesis predicts that there are a factor(s) in the blood of women with preeclampsia that are capable of altering endothelial cell function. We and others have examined in vitro interactions of maternal serum and endothelial cells to test this hypothesis. Our initial report indicating increased release of [51Cr]chromate from human umbilical vein endothelial cells (HUVE) suggested a lethal, lytic effect of serum from preeclamptic women. However, more specific indicators of endothelial cell structure and function do not support such a nonspecific effect. The morphology of HUVE was minimally altered after exposure to sera of preeclamptic women, and the entry of propidium iodide entry into cells, a sensitive indicator of membrane integrity, also was not increased. These findings, in combination with the increased expression of mRNA for platelet‐derived growth factor (PDGF), suggest endothelial cell activation rather than cell death in response to sera from preeclamptic women. Comparison of the effects of endotoxin and sera from preeclamptic women also supports the specificity of this response. Whereas endotoxin strikingly increased VWF on the surface of HUVE and tissue factor activity in conditioned media while minimally increasing cFN, preeclamptic sera increased cFN but had no demonstrable effect on VWF or tissue factor activity. Thus, under the conditions of our in vitro assays, sera from preeclamptic women are not diffusely toxic but rather act selectively on specific activation pathways.
Update on Immunotherapy for Recurrent Pregnancy Loss
Authors: COULAM CAROLYN B. , COULAM CURTIS H.
Published: May 2013

ABSTRACT: Results of recent, randomized, placebo‐controlled clinical trials have raised questions about the efficacy of immunotherapy for recurrent spontaneous abortion (RSA). Most of the clinical trials have shown a 70% successful pregnancy rate with immunotherapy. The controversy comes from variations in success rates in the control populations, which have ranged from 29% to 76%. Explanations for these variations includes small sample sizes and heterogeneity by the populations studied as well as cointervention by the placebo. A meta‐analysis has been proposed to investigate these explanations. Because the trials have largely used husband's leukocytes for immunization, alternative forms of immunotherapy have been sought. Two treatments that have been proposed but have not completed testing in randomized, placebo‐controlled trials are intravenous immunoglobulin (IVIG) and immunization with seminal plasma. A safe and efficacious method is needed to treat recurrent spontaneous abortion; it is hoped that results of proposed studies will answer this controversy.
Association Between Infertility and Spontaneous Abortion
Authors: COULAM CAROLYN B.
Published: May 2013

ABSTRACT: Women experiencing recurrent spontaneous abortion have a higher frequency of infertility than that expected in the general population. To further define the relationships between infertility and spontaneous abortion, the obstetrical histories of 43 women with unexplained secondary infertility were evaluated for the frequency of spontaneous abortion. Of the 88 pregnancies studied, 39 (44%) resulted in spontaneous abortion. Women with unexplained secondary infertility experienced a three‐fold increase (P < 0.0001) in the frequency of spontaneous abortions and half the number of live births (P < 0.0001) compared with the general population. We conclude that the association between infertility and spontaneous abortion includes a higher frequency of spontaneous abortion among infertile couples as well as a higher prevalence of infertility among recurrent spontaneous aborters compared with the general population.
Sperm Antibodies
Authors: PETERS ALBERT J. , COULAM CAROLYN B.
Published: May 2013

ABSTRACT: Antisperm antibodies (ASA) occur in 1% to 30% of infertile couples. Mechanisms by which ASA impair fertility include prevention of fertilization by decreasing acrosome reaction and/or zona pellucida binding, and postfertilization effects. Treatment for ASA involves assisted reproductive technologies.
A Rat Cytotrophoblast Antigen Defined by a Monoclonal Antibody
Authors: VERSTUYF A. , FONTEYN E. , SOBIS H. , VANDEPUTTE M.
Published: May 2013

ABSTRACT: A monoclonal antibody that recognizes specifically a cytotrophoblast antigen was obtained. The monoclonal antibody 22H6 was tested on rat choriocarcinoma (in vivo, in vitro), normal placenta, ectoplacental cone, blastocysts, and several normal organs. The antigen was detected on frozen sections and on tissue culture by indirect immunofluorescence. The monoclonal antibody 22H6 reacts with the cytotrophoblasts of rat choriocarcinoma. The giant cells do not display a positive reaction. It is not expressed on other tumors than choriocarcinoma. In adult rats the only cells revealing a positive reaction are the hepatocytes and the epithelial cells lining the small intestine. In the pregnant rat, the antigen is expressed on the cytotrophoblasts of the junctional zone in the placenta, but not on the giant cells. The mab reacts only with the small trophoblast cells of the ectoplacental cone, but not with trophectoderm of blastocyst. The mab has an IgG2b isotype and is not cytotoxic for choriocarcinoma cells in a complement‐dependent cytotoxicity test. The described monoclonal antibody is to our knowledge the only known marker of rat benign and malignant cytotrophoblast.
The Effect of Peritoneal Macrophage‐Derived Factor(s) on Ovarian Progesterone Secretion and LH Receptors: The Role of Calcium
Authors: CHEN THOMAS T. , LANE TERESA A. , DOODY MICHAEL C. , CAUDLE MICHAEL R.
Published: May 2013

ABSTRACT: Macrophages and their secretory products, cytokines, play an integral role in many reproductive processes. In this study we examined the effect of conditioned media from cultured human peritoneal macrophages on progesterone production by granulosa cells and the role of calcium in this process.

Macrophages were pretreated with various concentrations of a calcium channel blocker (verapamil) or a calcium ionophore (A23187). Macrophage‐conditioned media (MCM) or cell‐free media that contained calcium channel modifiers were added at three dose levels to cultured porcine granulosa cells. Progesterone production and LH receptor content were determined.

Macrophage‐conditioned media alone elevated basal progesterone production, but significantly attenuated granulosa cell LH receptor content. These effects were neither potentiated nor suppressed by pretreating macrophages with verapamil. However, production of the LH receptor lowering factor(s) appeared to be suppressed by calcium ionophore.

We conclude that (1) one or more factors produced by macrophages have a net stimulatory effect on basal progesterone production and these factor(s) may not be calcium‐dependent and (2) macrophage‐derived secretory products reduce granulosa cell LH receptor content. The production of these factor(s) may be calcium‐dependent.
Immunosuppression by Human Seminal Plasma&—Extracellular Organelles (Prostasomes) Modulate Activity of Phagocytic Cells
Authors: SKIBINSKI G. , KELLY R.W. , HARKISS D. , JAMES K.
Published: May 2013

PROBLEM: Prostasomes are trilamellar to multilamellar vesicles produced by the acinar cells of the human prostate and are present in appreciable amounts in normal human semen. The aim of this work was to study the effect of prostasomes on human polymorphonuclear cell and monocyte function.

METHODS: Functional activity of human neutrophils and monocytes was studied after incubation with prostasomes isolated from normal human seminal plasma. The following functional tests were employed: ability to ingest latex particles and opsonized bacteria (St. aureus) and ability to generate superoxide anion in response to PMA and FMLP. The latter was determined by measuring the super‐oxide‐dismutase inhibitable reduction of ferricytochrome c to ferrocytochrome c at 550 nm. Expression of cell surface markers and interactions of prostasomes with cells were studied by cytofluorimetry.

RESULTS: We show that prostasomes bind rapidly to the leukocyte cell membrane followed by internalization of adsorbed material. Interactions of prostasomes with neutrophils and monocytes inhibits their ability to phagocytose latex particles. The ability to ingest opsonized bacteria is, however, not impaired. Our results also show that incubation of leukocytes with prostasomes effectively inhibits superoxide anion generation in response to activation by PMA and FMLP.

CONCLUSIONS: Prostasomes may play a complementary role to other immunosuppressive factors contained in the human semen. They may protect sperm cells from deleterious effects of phagocytosing cells, prolong their life, and consequently enhance the chance of conception. At the same time prostasomes may have a permissive effect on sexually transmitted diseases.
Etiological Implication of Autoantibodies to Zona Pellucida in Human Female Infertility
Authors: KAMADA MASAHARU , DAITOH TOSHIFUMI , MORI KAZUMASA , MAEDA NOBUHIKO , HIRANO KOHIKO , IRAHARA MINORU , AONO TOSHIHIRO , MORI TAKAHIDE
Published: May 2013

PROBLEM: Autoantibodies to zona pellucida (ZP) have been implicated as a cause of infertility in woman by three lines of clinical and laboratory evidence.

METHOD: First, positive anti‐zona activities, as assessed by the passive hemagglutination reaction (PHAR) using bovine red blood cells sensitized with porcine zona antigen, were detected in 45 of 1,872 serum samples collected from infertile women, but in only three (two nonpregnant and one pregnant) of 592 serum samples from control subjects. Their incidence in 320 women with unexplained infertility (5.6%) was much higher than that in 1,552 women with infertility of known cause (1.7%, P < 0.01), which was comparable to the incidence observed in 193 age‐matched fertile nonpregnant and pregnant women (1.5%, P < 0.05). None of the serum samples from 292 age‐matched adult men and 100 children of between 5 and 10 years old gave a positive PHAR. Second, follow‐up study for a minimum of 2 years with treatment revealed that no pregnancy occurred in 11 infertile women with a consistently positive PHAR, and only three pregnancies in 19 infertile women with a fluctuating positive PHAR. Third, three of seven serum samples from women who gave a consistently positive PHAR produced strong immunofluorescence reactions on human ZP even after adsorption with porcine and human AB blood cells. Pre‐exposure of human ZP to the sera showing positive immunofluorescence, including that of one patient undergoing an in vitro fertilization program, greatly diminished the number of spermatozoa of normal quality that bound to and penetrated across human ZP.

CONCLUSIONS: The observed high incidence of anti‐zona activities and long‐term resistancy to treatment in women with unexplained infertility may be closely correlated with inhibition of sperm‐egg interaction by anti‐zona autoantibodies produced in these women.
Ontogeny of T Lymphocyte Function in the Neonate
Authors: WILSON CHRISTOPHER B. , PENIX LAURIE , WEAVER WILLIAM M. , MELVIN ANN , LEWIS DAVID B.
Published: May 2013

ABSTRACT: T cell precursors are first detected in the thymus at eight weeks of gestation. By 15 to 20 weeks of gestation, T‐cell precursors expressing αβ and γδ T‐cell receptors are present in the thymus in numbers relatively similar to those found in postnatal life. However, recent data suggest that T‐cell receptor diversity is more limited during fetal and neonatal life than in adults. Additionally, the functional capacity of T cells in the fetus and neonate is immature, in that neonatal T cells express a limited repertoire of lymphokines in response to activation. Specifically, the production of the lymphokines, interferon‐γ and interleukin‐4, which participate in the maturation of cytotoxic cells, activation of macrophages, and the maturation and modulation of B cell function and isotype expression, is reduced more than tenfold compared to cells from adults. This appears to result primarily from the lack of memory T cells in the fetus and neonate, reflecting their antigenic naivete. The difference in lymphokine expression is due to diminished transcription of these genes in neonatal T cells in response to activation. Preliminary data indicate that differences in essential promoter elements regulating transcription of these lymphokine genes plays a role in their differential expression in T cells.
NSAIDs: Maternal and Fetal Considerations
Authors: SCHOENFELD ALEX , BAR YACOB , MERLOB PAUL , OVADIA YARDENA
Published: May 2013

ABSTRACT: Nonsteroidal anti‐inflammatory drugs (NSAIDs) gained popularity in the late 1970s. Inhibition of prostaglandin synthesis with indomethacin has been reported to be effective for prevention of labor and for treatment for symptomatic polyhydramnios. Concern about its possible constrictive effect on the fetal ductus arteriosus has limited its use in pregnancy. Maternal indomethacin therapy has also been associated with reduction in urine production in the fetus and with oligohydramnios.

Obstetricians have discouraged pregnant women from taking analgesic doses of aspirin, mainly because of the availability of paracetamol (acetaminophen), which causes less gastric irritation, but also because of fear of maternal and fetal hemorrhage and of possible premature closure of the ductus. These fears largely derive from studies on patients taking large doses and from extrapolation from other NSAIDs. The likelihood that treatment with 60–75 mg/day of aspirin markedly reduces the incidence of preeclampsia and fetal intrauterine growth retardation makes it important to reexamine its use.

This review describes the pharmacology and pharmacokinetics of aspirin with particular reference to pregnancy and considers teratogenesis, prolongation of pregnancy and labor, maternal bleeding, fetal and neonatal bleeding, possible effects on the ductus arteriosus and pulmonary circulation, and possible nonspecific effects on intelligence and breast feeding and acute toxicity in the neonate.
Treatment With Immunosuppressive and Disease Modifying Drugs During Pregnancy and Lactation
Authors: OSTENSEN MONIKA
Published: May 2013

ABSTRACT: Active rheumatic disease may necessitate the treatment of pregnant and lactating patients with disease modifying (DMARD) or immunosuppressive drugs. This review summarizes data from the literature, and attempts to give some recommendations. Possible teratogenic effects of gold, penicillamine, and chloroquine are still disputed. As long as the issue is not settled, it seems prudent to stop using these agents as soon as pregnancy is diagnosed. Hydroxychloroquine has been used by some rheumatologists for treating pregnant patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) without malformations detected in the neonates. Sulphasalazine does not increase the rate of congenital abnormalities. Selected case reports have not shown any teratogenicity of cyclosporine A so far. However, the drug may cause fetal retardation. The use of standard doses of azathioprine does not increase the risk of congenital anomalies. By contrast, the antitumor agents cyclophosphamide, chlorambucil, and methotrexate are possibly teratogenic when given during early pregnancy, but may be less harmful in late pregnancy. Data on the excretion of DMARD and the cytostatic drugs are sparse. Because of insufficient data, breast feeding is not recommended in patients on antimalarials, penicillamine, cyclosporine A, and cytostatic drugs. Intramuscular gold and sulphasalazine seem to impose no major risk on the nursing infant.
Umbilical and Uterine Artery Flow Velocity Waveforms in Pregnant Women With Systemic Lupus Erythematosus Treated With Aspirin and Glucocorticosteroids
Authors: WEINER ZEEV , LORBER MARGALIT , BLUMENFELD ZEEV
Published: May 2013

ABSTRACT: Pregnancy in systemic lupus erythematosus (SLE) is at high risk to the mother and fetus. Impaired utero‐placental perfusion may increase fetal loss and intrauterine growth retardation. We assessed the changes in impedance to blood flow in the umbilical and uterine arteries in five patients with SLE treated with low dose aspirin and corticosteroids, using Doppler ultrasound longitudinally throughout pregnancy. Blood flow velocity waveforms of the umbilical and uterine arteries were studied by transabdominal and transvaginal Doppler ultrasound, respectively. Resistance index (RI) was measured every two to four weeks from week 10 to term, and the values obtained were compared to those of normal pregnancies. All five patients delivered uneventfully. One neonate was delivered at 36 weeks (2550 g) and one neonate was growth retarded (1900 g at 38 weeks). Three women delivered at 39 weeks (3585 g, 2850 g, and 2800 g). Most umbilical artery RI values obtained throughout pregnancy were above the 95th percentile of normal pregnancies. The highest values of RI of the umbilical artery were assessed in the case of fetal growth retardation. However, most measurements of RI of the uterine artery were under the 95th percentile of normal. The improved pregnancy outcome in patients with SLE treated with aspirin and corticosteroids seems to correlate with their normal uterine artery flow velocity wave forms.
Activation of the Complement Pathway: Comparison of Normal Pregnancy, Preeclampsia, and Systemic Lupus Erythematosus During Pregnancy
Authors: ABRAMSON STEVEN B. , BUYON JILL P.
Published: May 2013

ABSTRACT: To evaluate a flare of systemic lupus erythematosus (SLE) during pregnancy and to differentiate it from diseases of pregnancy, serological parameters are often utilized. However, there are conflicting reports regarding the merit of conventional measurements of complement and activation products. While in normal pregnancy the levels of serum C3, C4, and CH50 gradually rise, a decline in these levels occurs during the course of pregnancy in selected SLE patients. There is controversy regarding whether such falls represent decreases in the overall synthesis of complement or activation, the former theory being supported by a report of normal levels of the C1s‐C1 inhibitor complex. During normal pregnancies, increases of complement split products, such as plasma C3a, may occur, and these correlate positively with elevations of C3. In pregnancies complicated by lupus, increases of C3a are often accompanied by a decline in total C3 and CH50. In a minority of non‐SLE patients, preeclampsia has been associated with elevations of a variety of complement split products. Ba, C3a, C4d, SC5b‐9, indicating activation of both the classical and alternative pathways. The CH50 levels tend to remain normal in these patients. In contrast, elevations of complement split products frequently accompany disease flares in patients with SLE. A high ratio of CH50/Ba may differentiate patients with preeclampsia from those with active SLE. A decline in conventional measures of C3, C4, or CH50 which is accompanied by elevations of complement split products appears to differentiate a lupus flare from non‐SLE diseases of pregnancy.
Treatment of Patients With Antiphospholipid Antibodies During Pregnancy
Authors: MANY A. , PAUZNER R. , CARP H. , LANGEVITZ P. , MARTINOWITZ U.
Published: May 2013

ABSTRACT: Most authors agree upon the causal association between antiphosholipid antibodies [lupus anticoagulant (LAC) and/or anticardiolipin antibodies] and adverse pregnancy outcome. Placental insufficiency, caused by thrombosis, infarction and maldevelopment, is thought to be the main cause of fetal loss in patients with LAC. Therapy given thus far to prevent fetal loss can be divided into (1) immunosuppression by corticosteroids, azathioprine, or intravenous gamma globulin (IVGG), (2) anti‐aggregants to overcome imbalance of thromboxane/prostacycline production in patients with LAC, and (3) anticoagulants to neutralize the possible impairment of clotting inhibitor systems. Different therapeutic success rates have been reported by various authors who used the same combination of therapy. We report the results of different therapy regimens in 154 pregnancies in 31 women with LAC. These patients suffered from SLE with LAC or from APLA syndrome and experienced either recurrent miscarriages or thromboembolic phenomena in the past. With no therapy there were seven (6.8%) live births and 95 (93.2%) failures. Various combinations of corticosteroids, anti‐aggregants and anticoagulants were used for treatment. Of 52 treated pregnancies, 27 (51.9%) were successful. Sixteen (69.1%) of 23 pregnancies treated by all three modalities ended in live births. Four of these successful pregnancies occurred after failure of treatment by prednisone and anti‐aggregants only. In order to minimize osteoporosis caused by the combination of steroids and heparin, we have used warfarin in the second trimester and have lately substituted low molecular weight heparin for heparin. In the absence of a therapeutic schedule predicated on a large prospective study, therapy during pregnancy in patients having LAC should be individualized according to their obstetric and medical history. Anticoagulants are indicated in patients who have suffered from thromboembolic phenomena and could be tried after failure of steroids and anti‐aggregants.
Estrogens and Rheumatoid Arthritis
Authors: BIJLSMA J.W.J. , VAN DEN BRINK H.R.
Published: May 2013

ABSTRACT: Epidemiological and immunological evidence has suggested that female sex hormones may play a role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females.
The Effect of Pregnancy on Ankylosing Spondylitis, Psoriatic Arthritis, and Juvenile Rheumatoid Arthritis
Authors: OSTENSEN MONIKA
Published: May 2013

ABSTRACT: It has long been established that rheumatoid arthritis improves during pregnancy. The gestational course of other inflammatory arthritides like ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile rheumatoid arthritis (JRA) has been less well studied. The present review summarizes the results of our retrospective and prospective studies on the interaction between these diseases and pregnancy. The results showed clear differences for their gestational course. Patients with PsA improved or even remitted in 80% of the pregnancies, whereas 80% of the AS patients had unaltered or aggravated disease symptoms. The 20% of AS patients who markedly improved while pregnant all had AS with accompanying diseases like psoriasis, ulcerative arthritis, or small joint arthritis. Quiescent JRA was not reactivated by pregnancy, and active disease at conception ameliorated in about 60%. Fetal outcome was not adversely affected by AS, PsA, or JRA nor did there occur serious intercurrent diseases during pregnancy. In AS and PsA patients delivery was mainly uncomplicated. Sequelae of JRA were a frequent cause for cesarean section in JRA patients. A postpartum flare during the first 3 months after delivery occurred in about 90% of the AS pregnancies, 70% of the PsA pregnancies, and about 50% of the JRA pregnancies.
Pregnancy and Scleroderma
Authors: SILMAN ALAN J.
Published: May 2013

ABSTRACT: Scleroderma is a rare disease with a marked female excess in incidence. The pattern of age of onset, together with the effects of the disease, are such that the majority of women with scleroderma experience pregnancy prior to diagnosis. There are three questions of interest: (1) Does pregnancy adversely affect the prognosis of scleroderma? Isolated case reports suggest that renal disease, and in particular hypertensive crises, are associated with pregnancy in the absence of any renal abnormality before pregnancy. However, such events are rare. (2) Does scleroderma adversely affect either fertility or the outcome of pregnancy? Women with established scleroderma, again in case series, have a high rate of spontaneous miscarriage which is not found consistently in epidemiological studies. Prematurity and low birth rates are more frequent problems. (3) Does reproductive history influence disease susceptibility? Though early unrecognized disease and particularly Raynaud's phenomenon may antedate diagnosis by many years and might influence reproductive outcome, in general reproductive outcome is similar to that seen after diagnosis, although fertility appears to be reduced.
Mapping of the Familial Mediterranean Fever Gene to Chromosome 16
Authors: GRUBERG LUIS , AKSENTIJEVICH IVONA , PRAS ELON , KASTNER DANIEL L. , PRAS MORDECHAI
Published: May 2013

ABSTRACT: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever, synovitis, peritonitis, or pleurisy. Some patients eventually develop systemic amyloidosis. The biochemical cause of the disease is unknown. We have conducted a genome‐wide search for the FMF locus using 125 different DNA markers and mapped the FMF gene to the short arm of chromosome 16. The study was performed on 35 Israeli families primarily of North African and Iraqi origin. For the five markers D16S82 (p41‐1 Sacl), D16S80 (24‐1 Taq1), D16S84 (pCMM65 Taq1), D16S83 (pEKMDA2‐1 Rsal), and HBA (5′HVR Rsal) we obtained maximum lod scores of 2.72(θ = 0.08), 10.34 (θ = 0.04), 9.66 (θ = 0.050, 9.35 (θ = 0.03), and 14.31 (θ = 0.08), respectively. Multipoint analysis with HBA and D16S84 defined as a fixed loci gave a maximum lod score of 19.86 centromeric to D16S84. Crossovers defined by these markers place the FMF gene in an area of approximately 5 cM between D16S80 and D16S84. Other genes mapped to this area (16p13.3) include phosphodiesterase IB (PDE1B), hydroxyacyl‐glutathione hydrolase (HAGH), phosphoglycolate phosphatase (PGP), and the gene that causes adult polycystic kidney disease (PKD1). None of these genes bear an obvious pathophysiological relationship to FMF. Using additional markers from this region we hope to localize more precisely the FMF gene and to offer the possibility of prenatal diagnosis in selected cases. Our ultimate goal is to isolate and characterize the FMF gene.
Problem Areas of the Rheumatic Mother
Authors: OSTENSEN MONIKA , RUGELSJOEN ANNE
Published: May 2013

ABSTRACT: The extent to which women with rheumatic diseases are disabled in caring for their children is unknown. Fifty‐seven women with rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or systemic lupus erythematosus, all of whom had children under 6 years of age born during the disease, were interviewed. Patients with different diseases differed in their disabilities, but lifting, carrying, transporting, and bathing the child were difficult for most patients. Attention to these problem areas is necessary in the care of young mothers with rheumatic illness.
Target Antigens of the SSA/Ro and SSB/La System
Authors: BEN‐CHETRIT E.
Published: May 2013

ABSTRACT: The SSA/Ro and SSB/La antigens are polypeptides which serve as autoantigens in systemic lupus erythematosus and Sjogren's syndrome. The SSA/Ro contains two major isoforms of 60 kD and 52 kD. The former is the main native antigen while the latter is a major autoantigen in its denatured form. The SSB/La is a single phosphorylated protein of 48 kD. Recently a new protein of 46 kD, termed calregulin, was suggested as an additional component of the SSA/Ro antigens. However, extensive investigations failed to confirm its relation to the SSA/Ro system.

Based on molecular techniques and cDNA cloning of these antigens, it was demonstrated that the 60 kD protein is capable of binding RNA and DNA molecules, suggesting a regulatory role in transcription for this antigen. The 52 kD polypeptide contains multiple zinc finger motifs and its sequence is homologous to the mouse rptl protein, which is a T‐cell regulating peptide. The SSB/La is associated with precursors of 5S RNA and tRNA, implying that it has a role in the synthesis and maturation of RNA polymerase III transcripts.

The 60 kD and 52 kD SSA/Ro components may be associated within the cell. The SSA/Ro and SSB/La may also be in complex in some points of the cell cycle.
Neonatal Lupus Syndromes
Authors: BUYON JILL P.
Published: May 2013

ABSTRACT: Neonatal lupus is a model of passively acquired autoimmunity in that immune abnormalities in the mother lead to the production of antibodies that cross the placenta and injure the developing fetus. Congenital complete heart block (CCHB), a permanent manifestation of neonatal lupus, is detectable after 18 wk gestation. Transient manifestations include cutaneous, hepatic, and hematologic abnormalities that occur at variable frequency. To date, there is a universal association of CCHB with maternal antibodies to SSA/Ro‐SSB/La ribonucleoproteins, detectable by high ratio monomer:crosslinker SDS‐immunoblot. Intriguingly, cardiac disease and often other manifestations are not present in the mother, raising the hypothesis that there is differential expression and/or accessibility of SSA/Ro‐SSB/La antigens in fetal vs. adult tissues. CCHB may be a final consequence of a more widespread inflammatory response in the heart, including the existence of an associated myocarditis. In contrast to the in utero onset of CCHB, skin lesions generally become apparent after birth. Ultraviolet exposure may be an initiating factor and exacerbate an existing rash. Several studies have documented the predominance of DR3 alleles in mothers of affected offspring, frequently associated with the extended haplotype A1,B8. Available evidence suggests that fetal genetic differences in the major histocompatibility complex (MHC) do not influence susceptibility. The recommended clinical approach includes obstetric and rheumatologic management of both the fetus identified with CCHB and the fetus with a normal heart beat but at high risk of developing CCHB. Fetal echocardiogram is essential in diagnosing and following disease and may suggest the presence of an associated myocarditis. The rationale for treatment of identified CCHB and prevention of potential CCHB is to diminish a generalized inflammatory insult and lower the titer of maternal autoantibodies. Several intrauterine therapeutic regimens have been tried including dexamethasone and plasmapheresis but reversal of CCHB, once identified, has never been reported. The prior birth of a child with CCHB or other manifestations of neonatal lupus confers a greater risk of having a second affected child.
Autoantibodies in Normal and Abnormal Pregnancy
Authors: GLEICHER NORBERT
Published: May 2013

ABSTRACT: Abnormal autoimmune function has been associated with reproductive failure for decades. In fact, all medical conditions historically associated with pregnancy loss (and on occasion infertility) are now recognized to have an autoimmune etiology. It is therefore quite surprising that only less than a decade ago a correlation between the presence of abnormal autoantibodies and pregnancy loss was reported for the first time. Since reproductive failure, similar to other abnormal autoimmune states, is not a monoclonal event, we have established that affected patients demonstrate polyclonal autoantibody abnormalities including a variety of nonorganospecific as well as organspecific autoantibody groupings. For example, patients with repeated pregnancy loss will exhibit abnormal levels of anti‐phospholipid antibodies (PA).

In normal pregnancy natural autoantibodies do not follow the standard immunoglobulin (Ig) pattern, characterized by a decrease in levels despite a probably mild increase in production, which is excessively compensated by the vasodilatation of pregnancy. PA, especially, demonstrate a mild increase during pregnancy, though levels only in the peripartal period may reach abnormally high titers (in comparison to nonpregnant controls). This dichotomy between total Ig and natural autoantibodies is interesting since it suggests that autoantibodies may be under distinct control. In fact, we have suggested that this observed elevation of autoantibodies may be the result of an antigenic stimulus by self‐like antigen, represented by the maternal growth of the parasitic fetus.

In abnormal pregnancies, especially those associated with maternal hypertension and fetal growth retardation (IUGR), autoantibody levels do reach highly abnormal levels. We have reported that in both of these conditions significant abnormalities especially in IgG‐PA can be detected, which stand in direct correlation with severity of disease (though autoimmune hemolytic anemia (AHA) can also be found). This is an interesting observation because both of these conditions have been associated with an imbalance between thromboxane and prostacyclin in favor of the platelet aggregating and vasoconstrictive thromboxane. This is exactly the imbalance reported in women with habitual abortions, which is assumed to be PA‐induced. Aspirin, recently widely reported as being successful in the prevention of pregnancy‐induced hypertension (PIH) and IUGR, has also been recommended as treatment for habitual aborters. Lastly, habitual aborters who are successfully treated and reach viability in a subsequent pregnancy, experience a highly increased incidence of PIH and IUGR. All of these observations strongly suggest that PIH, IUGR, and repeated pregnancy loss may have a common pathophysiology. It is tempting to speculate that it is autoantibody—and especially PA—related.
Immune Reproductive Failure: Effect of Nonspecific Immunostimulation in Mouse Model
Authors: STRASSBURGER D. , CARP H. , TODER V.
Published: May 2013

ABSTRACT: There is much evidence that pregnancy loss may be immunologically mediated. Failure of the maternal immune system to actively support the pregnancy may be responsible for its demise. Potentiation of immune functions has been attempted in humans; however, the success of immunotherapy is still not clear. Thus immunotherapy experiments in mouse models are important. Nonspecific immunostimulation with complete Freund adjuvant (CFA) was shown in our laboratory to reverse the tendency to fetal loss in the CBA/J × DBA/2J mouse combination. CFA elevates the non‐T lymphocyte population, decreases T‐cell secreted lymphokines, and enhances macrophage‐secreted monokines. However, a relationship between these changes and a beneficial effect of CFA on reproductive performance has to be proved. Information obtained from nonspecific immunopotentiation in the CBA/J‐DBA/ 2J model may contribute the assessment of nonspecific immunotherapy in humans.
Specific Antiphospholipid Antibodies as a Predictive Variable in Patients With Recurrent Pregnancy Loss
Authors: AOKI KOJI , HAYASHI YAYOI , HlRAO YUKIE , YAGAMI YOSHIAKI
Published: May 2013

PROBLEM: Antiphospholipid antibodies (APLs) consist of very heterogenous autoantibodies. It has not been fully explored what kind of specificities are most relevant to recurrent pregnancy loss. Thus, we investigated the effects of specific APLs on recurrent aborters.

METHOD: IgG and IgM antibodies against PE (treated with 1% acetic acid) and five negatively‐charged phospholipids were measured by ELISA among 334 recurrent aborters without autoimmune disease. The relationships between APL specificities and subsequent pregnancy outcome were prospectively investigated in 38 recurrent aborters with positive APL who did not receive treatment with prednisolone and aspirin. Antibody levels exceeding the 99th percentile of 280 healthy women were considered positive.

RESULTS: Positive IgG and/or IgM APLs were detected in 14%, IgG APLs in 12%, and IgG antibodies against PA, PG, PI, PS, CL and PE, respectively, in 9%, 7%, 7%, 7%, 8%, and 8%. In a prospective study of the 38 untreated patients, fetal loss recurred in 82% of the 33 IgG APL‐positive patients, but in 40% of the five patients positive for only IgM APLs. The incidence of fetal loss in the next pregnancy of patients with IgG specific APL‐positive against PE, PI, PS, or CI was even higher at 90% and over, and fetal loss recurred in all of 21 patients with two or more IgG APL‐positive against PE, PI, PS, or CL.

CONCLUSION: These results suggest the possibility that two or more IgG APL‐positive value against treated PE, PI, PS, or CL, may be more accurate as a predictive variable than that of only one IgG APL‐positive in patients with recurrent pregnancy loss.
Treatment of Recurrent Spontaneous Abortion by Immunization With Paternal Lymphocytes: Results of a Controlled Trial
Authors: GATENBY PAUL A. , CAMERON KAYE , ADELSTEIN STEPHEN , SIMES R. JOHN , BENNETT MICHAEL J. , JANSEN ROBERT P.S. , SHEARMAN RODNEY P. , STEWART GRAEME J. , WHITTLE MELANIE , DORAN TREVOR J.
Published: May 2013

PROBLEM: It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded.

METHOD: A double‐blind placebo controlled trial was instituted in women with unexplained recurrent spontaneous abortion, comparing immunization with 400 million paternal to 400 million maternal (autologous) lymphocytes. The groups were compared in a paired sequential trials chart, by logistic regression, and, in addition, a meta‐analysis of this and other published trials was carried out.

RESULTS: The live birth rate among pregnancies in paired couples with paternal lymphocyte immunization was 68% compared to 47% in the women who received their own cells. The results bordered on, but did not achieve, statistical significance. The women in each group were thoroughly investigated to exclude known causes of recurrent pregnancy loss and appeared to have been well matched in all variables. Women with lymphocytotoxic antibodies against paternal lymphocytes were excluded. Unlike our previous study there was not association between the time to conception and the chance of a successful outcome. Indeed, the time to conception was relatively short, 12 wk in all groups. The meta‐analysis supported an overall modest favorable experience with paternal cells.

CONCLUSION: The study is consistent with a general trend favoring paternal over maternal lymphocyte immunization but reinforces the need for larger multicenter controlled trials as well as more detailed biological study in humans to understand the nature of the maternal‐fetal interface and its breakdown.
The Use of ELISA to Evaluate Human Antibody Binding to Epididymal Sperm From Different Species
Authors: FICHOROVA RAINA N. , NAKOV LYUDMIL S.
Published: May 2013

PROBLEM: The impact of antibodies to epididymal sperm antigens in human infertility has been poorly understood. Cross‐reactivity of human antibodies with animal epididymal sperm has been previously observed, however, only by means of qualitative methods. Moreover, it has been always compared to reactivity against human ejaculated rather than human epididymal sperm.

METHOD: Following a screening study of 940 infertility patients, sperm agglutinating and immobilizing sera as well as sperm anbitody negative controls were used to standardize an ELISA employing human ejaculated sperm. Nine sera positive in ELISA were further tested against epididymal human, guinea pig, rat, and hamster sperm. Differences among groups were evaluated by factorial analysis of variance (ANOVA).

RESULTS: The specificity and sensitivity of ELISA were shown to be 85.1% and 61.18%, respectively. Eight out of nine antisperm antibody‐positive sera from infertile subjects reacted relatively stronger with epididymal than with ejaculated human sperm. All tested infertility sera showed strong although variable cross‐reactivity with sperm from guinea pig, hamster, and rat.

CONCLUSION: ELISA has definite potential in sperm antibody research, allowing quantitative assessment of the results and immotile sperm employment. The suggested predominant role of epididymal sperm antigens in immune responses related to fertility needs further investigation. Some of these antigens are obviously phylogenetically perserved, and possibly in a quantitative aspect present differently on epididymal spermatozoa from various mammalian species.
The Effect of Aspirin on Recurrent Fetal Loss in Experimental Antiphospholipid Syndrome
Authors: KRAUSE ILAN , BLANK MIRI , GILBRUT BORIS , SHOENFELD YEHUDA
Published: May 2013

PURPOSE: To evaluate the effect of aspirin treatment upon fetal loss in mice with experimental antiphospholipid syndrome (APLS).

MATERIALS AND METHODS: Experimental APLS was induced in pregnant mice by passive transfer of mouse monoclonal anticardiolipin antibody. The mice were treated with high (100μg/d) or low (10μg/d) does of aspirin, using vitaminC(100μg/d or 10μg/d)as a control. The mice were assessed for the presence of lupus anticoagulants (prolonged aPTT), thrombocytopenia, degree of fetal resorption rate and mean embryo and placental weights.

RESULTS: The mice with APLS had a higher fetal resorption rate(45.7± 12.2% vs 2.5 ± 0.4%, P<0.001), reduced placenta mean weight(104 ± 8 mgvs 169 ±7mg, P<0.001), prolonged aPTT (94± 14sec vs 39±4sec, P<0.001), and reduced mean platelet count(597± 186 ± 103/mm3vs 847±51 ± 103/mm3,P<0.001). The groupof mice with APLS, who were treated with low‐dose aspirin, had a lower resorption rate (11.1 ±9.3% vs 45.7±12.2%, P<0.001), a higher placenta mean weight (178 ± 8 mg vs 104 ± 8 mg, P<0.001), a higher mean embryo weight (1042 ± 134 mg vs 721±91 mg, P<0.001), and a lower aPTT (58±15 sec vs 94±14 sec, P, <0.001). Micewho were treated with high‐dose aspirin also had a lower resorption rate, although not as much as in the low‐dose aspirin group (34.2 ± 12.7% vs 45.7 ± 12.2%, P<0.001).

CONCLUSION: Aspirin, especially in low dose, has a protective effect against obstetrical complications associated with experimental APLS.
Maternal‐Fetal Histocompatibility in Intrauterine Growth Retarded and Normal Weight Babies
Authors: VERP MARION S. , SIBUL MARK , BILLSTRAND CHRIS , BELEN GARY , HSU MICHAEL , OBER CAROLE
Published: May 2013

PROBLEM: To determine whether risk for intrauterine growth retardation (IUGR) is increased in HLA‐DQA1 compatible pregnancies.

METHOD: Paired maternal and cord blood samples were obtained from 30 IUGR and 31 non‐IUGR pregnancies delivered at a university hospital. Samples were typed for eight HLA‐DQA1 alleles using 10 sequence‐specific oligonucleotide probes. Associations between IUGR and HLA‐DQ compatibility status, and other risk factors were examined using logistic regression analysis.

RESULTS: HLA‐DQ compatibility and history of spontaneous abortion were not individually significant risk factors for IUGR; however, there was an interactive effect between these two factors and IUGR (P = 0.085) that improved the overall fit of the logistic model (P < 0.001). No individual allele was more common in IUGR pregnancies.

CONCLUSION: HLA compatibility per se is not associated with sufficient inhibition of fetal growth to result in IUGR as defined. However, in women with a history of spontaneous abortion, HLA compatibility may have an effect.
Murine Trophoblast Failure and Spontaneous Abortion
Authors: CLARK DAVID A. , BANWATT DALJEET , CROY B. ANNE
Published: May 2013

PROBLEM: Infection has been proposed to initiate abortion, and the role of viruses in spontaneous resorption in mice has not been tested.

METHOD: The anti‐viral drug ribavirin (1‐β‐D‐ribofuranosyl‐1,2,4‐triazole‐3‐carboxamide) was fed to CBA/J and C3H/HeJ female mice beginning on the morning after mating with DBA/2J males.

RESULTS: Ribavirin treatment increased the rate of abortion (resorption) on day 13.5, and this was associated with retardation of the rate of embryo development and hypoplasia of the trophoblast. There was a reduction in trophoblast‐dependent decidua‐associated soluble suppressor activity, but there was no maternal mononuclear cell infiltrate of the type reported in association with resorption of semiallogeneic and xenogeneic mouse embryos. This may be due to an immunosuppressive effect of ribavirin. Ribavirin was able to potently suppress proliferation of mouse trophoblast and mastocytoma cell lines in vitro.

CONCLUSIONS: There are several drug‐induced murine abortion models that provide useful insights into potential mechanisms underlying spontaneous pregnancy failure, but in the ribavirin model, a direct impairment of trophoblast development appears to be responsible.
In Vitro Effect of Anticardiolipin Autoantibodies Upon Total and Pulsatile Placental hCG Secretion During Early Pregnancy
Authors: SHURTZ‐SWIRSKI R. , INBAR O. , BLANK M. , COHEN J. , BAKIMER R. , BARNEA E.R. , SHOENFELD Y.
Published: May 2013

BACKGROUND: The anticardiolipin syndrome is characterized among other features by recurrent thromboembolic events, thrombocytopenia, and recurrent fetal loss associated with high IgG titers of anticardiolipin antibodies and/or the presence of lupus anticoagulant. AIMS: The mechanisms for the fetal loss in this syndrome have not yet been clearly elucidated, although several hypotheses based on experimental data have been put forward. We wanted to evaluated the effect in vitro of anticardiolipin antibodies on the secretion of human chorionic gonadotropin.

METHODS: Employing our previous experience with placental explants, we studied the effect of several mouse monoclonal and human polyclonal purified anticardiolipin antibodies (ACA), which were shown by us to induce experimental antiphospholipid syndrome (APLS), to affect the pulsatile secretion of beta human choriogonadotropin.

RESULTS: The mouse monoclonal ACA antibodies caused an increase in the pulsatility of beta human choriogonadotropin, while human polyclonal ACA derived from patients with ACA had an inhibitory effect.

CONCLUSION: These studies with placental explants show that ACA may have an additional effect on placental hormone secretion and thus affect the fate of the embryo.
Hormonal Regulation of the Secretory IgA (sIgA) System: Estradiol‐ and Progesterone‐induced Changes in sIgA in Parotid Saliva Along the Menstrual Cycle
Authors: GÓMEZ ENRIQUE , ORTIZ VÍCTOR , SAINT‐MARTIN BLANCA , BOECK LOURDES , DÍAZ‐SÁNCHEZ VICENTE , BOURGES HÉCTOR
Published: May 2013

The effect of estradiol (E2) and progesterone (P4) on the IgA system, both at the systemic and at the mucosal level, was studied in 10 healthy young adult Mexican women during two consecutive menstrual cycles (MC); the control group consisted of five young adult Mexican men. Eight matched samples of blood and parotid saliva were obtained, in which serum E2, P4, and IgA were quantified. Parotid saliva was obtained with Curby's device and sIgA was quantified by an ELISA method. The MC was divided into follicular phase (FP, days 1 to 16) and luteal phase (LP, days 17 to 30). Serum IgA showed slight fluctuations along the period of study, but they were not different between women and men. Irrespective of the phase of the MC, salivary sIgA was higher in women than in men (P<0.01); sIgA was slightly but not significantly higher in the FP, as compared to the LP. The comparison of phases in each individual woman showed significantly higher levels in the FP (P<0.01). The profile of sIgA in saliva observed in women resembled the pattern of serum E2 (r = 0.859, P<0.05), suggesting a possible relation of E2 in the secretion of sIgA by the parotid gland.