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Biomedical subjects

D W Branch

Publications and source records attributed to D W Branch.

At least 37 records · Page 2Linked to original sources
PubMed1999

Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance.

OBJECTIVE: To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes. METHODS: Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with > or =2 affected members were analyzed by segregation analysis and typed for candidate genetic markers. RESULTS: Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS. Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes. CONCLUSION: Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including beta2-glycoprotein 1, HLA, T cell receptor beta chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.

Adolescent↗
PubMed1999

Anti-beta2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome.

OBJECTIVE: Studies in rheumatologic and hematologic populations suggest that anti-beta(2)-glycoprotein I antibodies are more specific for the clinical manifestations of antiphospholipid syndrome than anticardiolipin antibodies. However, the association between anti-beta(2)-glycoprotein I and pregnancy loss remains uncertain. We sought to determine whether anti-beta(2)-glycoprotein I is associated with the obstetric features of antiphospholipid syndrome. STUDY DESIGN: Sera from 4 groups of women were studied: (1) 152 healthy fertile control subjects, (2) 141 subjects with unexplained recurrent spontaneous abortions, (3) 58 subjects with unexplained fetal deaths, and (4) 73 subjects with well-characterized antiphospholipid syndrome. Serum anticardiolipin and anti-beta(2)-glycoprotein I levels were determined by enzyme-linked immunoassay. RESULTS: Patients with antiphospholipid syndrome had significantly higher levels of immunoglobulin G and immunoglobulin M anticardiolipin and anti-beta(2)-glycoprotein I than the other 3 groups (P <.0001). However, women in the recurrent spontaneous abortion, fetal death, and fertile control groups had similar levels of each antibody. Similarly, there were no differences in the proportion of women with positive test results for each autoantibody in these 3 groups. Linear regression analysis showed significant correlation between anticardiolipin immunoglobulin G and beta(2)-glycoprotein I immunoglobulin G (R (2) = 0.544786, P =.0001) and anticardiolipin immunoglobulin M and beta(2)-glycoprotein I immunoglobulin M (R (2) = 0.525048, P =.0001). CONCLUSION: Both anticardiolipin and anti-beta(2)-glycoprotein I are associated with antiphospholipid syndrome. However, testing for anti-beta(2)-glycoprotein I does not identify additional patients with either recurrent spontaneous abortions or unexplained fetal deaths who initially have negative test responses for anticardiolipin. This is likely because of the strong correlation between the 2 autoantibodies. Our data do not support routine testing for anti-beta(2)-glycoprotein I in addition to testing for antiphospholipid antibodies in women with recurrent pregnancy loss and unexplained fetal death.

Abortion, Habitual↗
PubMed1999

Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy.

OBJECTIVE: To assess maternal and fetal outcomes in 15 patients with antiphospholipid syndrome (19 pregnancies) treated with intravenous immunoglobulin (IV Ig) during pregnancy. METHODS: Monthly IV Ig therapy was initiated in the first or early second trimester of all pregnancies except two. Additional therapy consisted of low-dose aspirin and subcutaneous heparin. Six patients also received steroid therapy. Serial anticardiolipin IgG levels were measured in eight pregnancies. RESULTS: The live-birth rate was 84% (16 of 19 live births), and there were three pregnancy losses. There were no cases of fetal growth restriction (FGR). Preeclampsia and nonreassuring fetal status were each diagnosed in 25% of the pregnancies. Seventy-five percent of the infants were delivered at 34 weeks' gestation or later. Anticardiolipin IgG decreased throughout the course of therapy in seven pregnancies. Placental pathology was minimal. CONCLUSION: Pregnancy complications appear to be minimized with the use of IV Ig. Definitive recommendations regarding the use of IV Ig in pregnancy await the conclusion of randomized trials. If the combination of IV Ig, aspirin, and heparin significantly decreases the incidences of FGR and prematurity, it may be a cost-effective primary therapy for pregnancies complicated by the antiphospholipid syndrome.

Adult↗
PubMed1999

Microcontact printing for precise control of nerve cell growth in culture.

Microcontact printing, facilitated by silane linker chemistry and high-relief stamps, creates precise patterns of proteins, which in turn control growth of hippocampal neurons in culture. This additive, multi-mask technique permits several different molecules to be patterned on the same substrate. The covalent linker technology permits relatively long-term (two-week) compliance of neurons to the stamped pattern against a polyethylene glycol background. When polylysine was stamped adjacent to a laminin/polylysine mixture, neural somata and dendrites preferred the polylysine while axons prefer the mixture or the border between the two.

Animals↗
PubMed1998

Microstamp patterns of biomolecules for high-resolution neuronal networks.

A microstamping technique has been developed for high-resolution patterning of proteins on glass substrates for the localisation of neurons and their axons and dendrites. The patterning process uses a microfabricated polydimethylsiloxane stamp with micrometer length features to transfer multiple types of biomolecules to silane-derivatised substrates, using glutaraldehyde as a homobifunctional linker. To test the efficacy of the procedure, substrates are compared in which poly-d-lysine (PDL) was physisorbed and patterned by photoresist with those stamped with PDL. Fluorescein isothiocyanate labelled poly-l-lysine was used to verify the presence and uniformity of the patterns on the glass substrates. As a biological assay, B104 neuroblastoma cells were plated on stamped and physisorbed glass coverslips. Pattern compliance was determined as the percentage of cells on the pattern 8 h after plating. Results indicate that the stamping and photoresist patterning procedure are equivalent. Substrates stamped with PDL had an average pattern compliance of 52.6 +/- 4.4%, compared to 54.6 +/- 8.1% for physisorbed substrates. Measures of background avoidance were also equivalent. As the procedure permits successive stamping of multiple proteins, each with its own micropattern, it should be very useful for defining complex substrates to assist in cell patterning and other cell guidance studies.

Cell Biology↗
PubMed1998

Thyroid autoantibodies are not associated with recurrent pregnancy loss.

OBJECTIVE: Approximately 1% of all women have recurrent pregnancy loss, defined as >/=3 spontaneous losses of pregnancy; however, a cause is determined in only 50% of cases. Recent studies have associated the presence of thyroid autoantibodies during the first trimester of pregnancy with spontaneous abortion in the current pregnancy among women without a history of recurrent abortion. The objective of this study was to determine whether circulating thyroid autoantibodies were associated with recurrent pregnancy loss. STUDY DESIGN: Sera from 74 nonpregnant women with a history of recurrent pregnancy loss and from 75 healthy, fertile control subjects of similar gravidity were tested for thyroglobulin and thyroid peroxidase antibodies by means of radioimmunoassay kits. All women had a third-generation thyroid-stimulating hormone assay performed. Samples were obtained >/=6 months after a pregnancy. RESULTS: Twenty-two of the women with a history of recurrent pregnancy loss (29.3%) and twenty-eight of the control subjects (37%) had positive results for either one or both of the thyroid autoantibodies (P >. 05). Mean thyroid-stimulating hormone levels and the proportion of women with abnormal thyroid-stimulating hormone values did not differ between the 2 groups. CONCLUSION: Women with a history of recurrent pregnancy loss are no more likely than are fertile control subjects to have circulating thyroid autoantibodies. Testing for antithyroid antibodies is not clinically useful in the evaluation of patients with a history of recurrent pregnancy loss.

Abortion, Habitual↗
PubMed1998

Antiphospholipid antibodies and reproductive outcome: the current state of affairs.

Antiphospholipid antibodies were first linked to pregnancy loss more than 20 years ago, and the condition known as antiphospholipid syndrome is perhaps the most convincing 'immunologic' disturbance other than anti-erythrocyte and anti-platelet alloimmunization disorders. Specific criteria for the antiphospholipid syndrome have been delineated, the anticardiolipin assay has been standardized, and authorities agree on laboratory criteria defining lupus anticoagulant. Nonetheless, considerable confusion exists regarding antiphospholipid syndrome and related reproductive problems. The state of affairs primarily derives from two problems: the first is the premature introduction of non-standardized antiphospholipid assays into clinical use without rigorous standardization and prior to convincing proof of clinical utility. As a result, well-intending, but less well-versed clinicians sometimes make the diagnosis of antiphospholipid syndrome in women who are negative for lupus anticoagulant and anticardiolipin antibodies. This is especially confusing in the face of of growing evidence that the relevant in vivo antiphospholipid antigen is formed by a complex between beta 2-glycoprotein 1 and phospholipids. A second major problem is that of unwarranted discrepancies in the clinical and laboratory features of patients considered to have a diagnosis of antiphospholipid syndrome. This problem is most apparent in the case selection for pregnancy-loss treatment series and trials. Many series have included women with predominantly pre-embryonic and embryonic pregnancy losses, while others included a large majority of patients with one or more second or third trimester pregnancy losses. Some treatment trials purposefully excluded patients with a history of thrombosis or systemic lupus erythematosus, features found in nearly 50% of patients in other series. Though most authorities require the presence of either lupus anticoagulant or medium-to-high titer IgG anticardiolipin antibodies to make a diagnosis of antiphospholipid syndrome, in some series no more than half of the study patients had lupus anticoagulant and as many as 20% had only IgM anticardiolipin antibodies. It is very unlikely that patients with such disparate clinical and laboratory findings have the same autoimmune syndrome, and a stated or implicit diagnosis of antiphospholipid syndrome in such a wide variety of women is scientifically unsound and clinically dangerous. The relationship between antiphospholipid antibodies and poor reproductive outcomes must be approached through rigorous scientific study and appropriate treatments established by well-designed clinical trials.

Abortion, Habitual↗
PubMed1998

Effect of antiphospholipid antibodies on beta(2) glycoprotein I-phospholipid Interaction.

PROBLEM: Beta(2)glycoprotein I (beta(2)GPI) physiologically binds to negatively charged phospholipids (PLs) and is a natural regulator of the coagulation cascade. Thrombotic clinical complications and recurrent fetal loss associated with autoimmune antiphospholipid (aPL) antibodies are thought to be related to their binding to Beta(2)GPI-PL complex and interference with the physiological function of Beta(2)GPI. METHOD OF STUDY: To investigate the effect of aPL on beta(2)GPI-PL interaction, we studied the binding of biotinylated Beta(2)GPI to cardiolipin (CL) by enzyme-linked immunosorbent assay (ELISA) in the presence and absence of purified aPL immunoglobulin G (IgG) antibodies. RESULTS: Adding five different aPL IgG antibodies with different levels of aPL activity isolated from the sera of five patients with aPL-associated recurrent fetal death greatly increased the binding of biotinylated beta(2)GPI to CL-coated plates. The optical densities (ODs) were 0.635, 0.890, and 1.265 in the presence of three aPL IgG antibodies, compared to 0.425 in the absence of aPL IgG. In contrast, normal human IgG had no enhancing effect. The OD was 0.480 and 0.425, respectively. The enhancement of beta(2)GPI binding to CL by aPL IgG correlated with the titers of aPL antibodies. The use of phosphate-buffered saline with increasing salt concentrations as a washing buffer for the ELISA resulted in more stable binding of beta(2)GPI to PL in the presence of aPL IgG. CONCLUSIONS: These findings suggest that the binding of autoimmune aPL antibodies to beta(2)GPI-PL complex results in abnormally tighter interaction between beta(2)GPI and PLs, which may lead to physiological dysfunction of beta(2)GPI as a regulator of coagulation.

Antibodies, Antiphospholipid↗
PubMed1998

Anticoagulant treatment during pregnancy: an update.

During pregnancy and the immediate puerperium, the risk for venous thromboembolism (VTE) is substantially increased. Certain medical conditions, including inherited or acquired thrombophilias, and obstetric manipulations such as cesarean delivery further increase this risk. Consequently, acute VTE is one of the leading causes of maternal morbidity and direct mortality in the United States and other developed countries. That considered, clinicians and researchers must understand how to effectively use anticoagulant drugs during pregnancy, and must recognize areas for improvement in the knowledge of these medications. These areas are especially important, because the use of anticoagulants during pregnancy may even increase in light of recent information indicating that thrombophilia is associated with certain more common obstetrical complications.

Anticoagulants↗
PubMed1997

The epitopes for some antiphospholipid antibodies are adducts of oxidized phospholipid and beta2 glycoprotein 1 (and other proteins).

Circulating autoantibodies to phospholipids (aPLs), such as cardiolipin (CL), are found in patients with antiphospholipid antibody syndrome (APS). We recently demonstrated that many aPLs bound to CL only after it had been oxidized (OxCL), but not to a reduced CL analogue that could not undergo oxidation. We now show that the neoepitopes recognized by some aPLs consist of adducts formed between breakdown products of oxidized phospholipid and associated proteins, such as beta2 glycoprotein 1 (beta2GP1). Addition of human beta2GP1, polylysine, native low-density lipoprotein, or apolipoprotein AI to OxCL-coated wells increased the anticardiolipin antibody (aCL) binding from APS sera that first had been diluted so that no aCL binding to OxCL could be detected. No increase in aCL binding was observed when these proteins were added to wells coated with reduced CL. The ability of beta2GP1, polylysine, or low-density lipoprotein to be a "cofactor" for aCL binding to OxCL was greatly reduced when the proteins were methylated. Incubation of beta2GP1 with oxidized 1-palmitoyl-2-linoleyl-[1-14C]-phosphatidylcholine (PC), but not with dipalmitoyl-[1-14C]-PC, led to formation of covalent adducts with beta2GP1 recognized by APS sera. These data suggest that the reactive groups of OxCL, such as aldehydes generated during the decomposition of oxidized polyunsaturated fatty acids, form covalent adducts with beta2GP1 (and other proteins) and that these are epitopes for aCLs. Knowledge that the epitopes recognized by many aPLs are adducts of oxidized phospholipid and associated proteins, including beta2GP1, may give new insights into the pathogenic events underlying the clinical manifestations of APS.

Antibodies, Antiphospholipid↗
PubMed1997

Variable effects on murine pregnancy of immunoglobulin G fractions from women with antiphospholipid antibodies.

OBJECTIVE: Initial studies showed that passive immunization with human immunoglobulin G fractions containing antiphospholipid antibodies can result in murine fetal loss. We intended to use the murine model to study mechanisms of fetal loss associated with antiphospholipid antibodies. However, we have since found variable effects of antiphospholipid antibodies on murine pregnancy. The objective of this study was to determine the consistency of murine pregnancy loss from antiphospholipid antibody containing immunoglobulin G fraction. STUDY DESIGN: Pregnant C3H/HeN (mated with C57B1/6 males) and BALB/c (mated with BALB/c males) mice were passively immunized with antiphospholipid antibody containing human immunoglobulin G fraction from 20 women with antiphospholipid syndrome. The mice received either a single dose of 10 to 30 mg on day 12 of pregnancy or 10 mg per day on days 12 to 14 of gestation. Some mice receiving each dose of immunoglobulin G fraction were bled to confirm serum levels of anticardiolipin antibodies. Mice were killed on day 15 and the fetal status was determined. RESULTS: Overall, passive immunization with individual antiphospholipid antibody containing immunoglobulin G fractions resulted in 801 live pups (75%), 232 fetal deaths (22%), and 38 resorptions (3%) in 131 mice. The effect of immunoglobulin G fractions from individual patients was highly variable. Immunoglobulin G fraction from eight women resulted in high rates of fetal loss. However, in spite of high levels of anticardiolipin antibodies, fetal outcome was normal in mice immunized with immunoglobulin G fraction from the majority of women. The rate of fetal death did not uniformly increase with increasing doses of immunoglobulin G fraction and was unrelated to the donor's medical history. Fetal outcome was similar for both C3H/HeN and BALB/c mice. CONCLUSIONS: Human antiphospholipid antibodies have variable effects on murine pregnancy outcome. Characterization of antiphospholipid antibodies that do and do not cause murine fetal loss may provide insight into epitopes relevant to fetal loss associated with antiphospholipid syndrome.

Adult↗
PubMed1997

Bacterial lipopolysaccharide-mediated murine fetal death: the role of interleukin-1.

OBJECTIVE: Our purpose was to determine whether interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and, if so, whether interleukin-1 causes fetal death by inducing prostanoid formation in gestational tissues. STUDY DESIGN: Pregnant C3H/HeN mice were administered lipopolysaccharide, interleukin-1alpha, interleukin-beta, or vehicle on days 11 to 13 of pregnancy. Mice were killed 72 hours later and the fetal status was determined. Some mice were pretreated with anti-interleukin-1-receptor antibodies or indomethacin. Decidual explants were established from treated mice, and supernatants were assayed for interleukin-1beta and prostaglandin E2. RESULTS: Decidua taken from lipopolysaccharide-treated mice produced significantly increased amounts of interleukin-1beta, and pretreatment with anti-interleukin-1-receptor antibodies reduced the proportion of fetal deaths after lipopolysaccharide administration from 100% to 33%. The administration of interleukin-1alpha caused fetal death in a dose-dependent fashion, and decidua taken from interleukin-1-treated mice produced significantly increased amounts of prostaglandin E2. However, pretreatment with doses of indomethacin that abrogated decidual prostaglandin E2 production did not reduce the proportion of fetal death after interleukin-1alpha administration. CONCLUSIONS: Interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and causes fetal death by prostaglandin-independent effects.

Animals↗
PubMed1997

Pathogenic antibodies in women with obstetric features of antiphospholipid syndrome who have negative test results for lupus anticoagulant and anticardiolipin antibodies.

OBJECTIVE: Our goal was to determine whether women with clinical features of antiphospholipid syndrome but negative test results for lupus anticoagulant and anticardiolipin antibodies have pathogenic antibodies not identified by currently used methods. STUDY DESIGN: Sera were obtained from women with clinical features associated with antiphospholipid antibodies who had negative test results for lupus anticoagulant and anticardiolipin antibodies (antiphospholipid syndrome-like). We studied (1) the effect of passive immunization with their purified immunoglobulin G fraction on murine pregnancy (n = 35) and (2) the presence of antiphospholipid antibodies other than lupus anticoagulant or anticardiolipin antibodies (n = 39). Sera were also retested for anticardiolipin antibodies and lupus anticoagulant. RESULTS: Fetal loss occurred in 235 of 1088 (22%) pups in 137 mice immunized with immunoglobulin G fraction from antiphospholipid syndrome-like women compared with 23 of 402 (6%) pups in 53 control mice. Immunoglobulin G from 11 study patients resulted in the loss of at least one third of the exposed pups. Five women had positive levels of antiphosphatidylserine antibodies (>99th percentile). All levels were low positive, and three women also had low-positive levels of anticardiolipin antibodies on repeat testing. Five of the 11 (45%) women whose immunoglobulin G fractions caused at least 33% fetal loss also had positive test results for antiphospholipid antibodies. CONCLUSIONS: A subset of women with clinical disorders suspicious for antiphospholipid syndrome but who had negative test results for lupus anticoagulant and anticardiolipin antibodies by current methods have serum immunoglobulin G that is pathogenic to murine pregnancy. Testing for pathogenic immunoglobulin G may provide additional means to identify women with an as yet uncharacterized immune condition. The clinical relevance of low levels of antiphospholipid antibodies in these women remains unproved.

Abortion, Habitual↗
PubMed1997

Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome.

OBJECTIVE: To determine whether antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin are associated with recurrent pregnancy loss. METHODS: Sera from three groups of women were studied: 1) 147 women with recurrent pregnancy loss but no clinical signs or symptoms of autoimmune disease who tested negative for lupus anticoagulant and medium-to-high levels of immunoglobulin G anticardiolipin antibodies; 2) 104 healthy, fertile controls of similar age and gravidity; and 3) 43 women with well-characterized antiphospholipid syndrome. Serum antibody binding against six phospholipids (cardiolipin, phosphatidic acid, phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol) was determined using enzyme-linked immunoassays, and results were normalized using an anticardiolipin standard. RESULTS: Twenty-six (18%) women with recurrent pregnancy loss and nine (9%) controls tested positive (above the 99th percentile) for antiphospholipid antibodies. Sera from five (3.4%) women with recurrent pregnancy loss and four (3.8%) controls demonstrated binding to phospholipid antigens other than cardiolipin. In contrast, binding to phospholipid antigens was demonstrated in sera from more than 90% of women with antiphospholipid syndrome. Among women testing positive for antiphospholipid antibodies, the median positive value for women in the antiphospholipid syndrome group was significantly higher than for those with recurrent pregnancy loss or normal fertile controls. CONCLUSIONS: Women with recurrent pregnancy loss are no more likely than fertile controls to have elevated levels of antiphospholipid antibodies once lupus anticoagulant, anticardiolipin, and an obvious clinical history of autoimmune disease have been excluded. Testing for antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin is not clinically useful in the evaluation of recurrent pregnancy loss.

Abortion, Habitual↗