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Biomedical subjects

S Lederman

Publications and source records attributed to S Lederman.

At least 55 records · Page 3Linked to original sources
PubMed1991

A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4.

The CD4 molecule is a relatively non-polymorphic 55 kDa glycoprotein expressed on a subset of T lymphocytes. A common African allele of CD4 has been identified by non-reactivity with the monoclonal antibody, OKT4. The genetic basis for the OKT4- polymorphism of CD4 is unknown. In the present paper, the structure of the CD4 molecule from an homozygous CD4OKT4- individual was characterized at the molecular level. The size of the CD4OKT4- protein and mRNA were indistinguishable from those of the OKT4+ allele. The polymerase chain reaction (PCR) was used to map the structure of CD4OKT4- cDNAs by amplifying overlapping DNA segments and to obtain partial nucleotide sequence after asymmetric amplification. PCR was then used to clone CD4OKT4- cDNAs spanning the coding region of the entire, mature CD4 protein by amplification of two overlapping segments followed by PCR recombination. The nucleotide sequence of CD4OKT4- cDNA clones revealed a G----A transition at bp 867 encoding an arginine----tryptophan substitution at amino acid 240 relative to CD4OKT4+. Expression of a CD4OKT4- cDNA containing only this transition, confirmed that the arginine----tryptophan substitution at amino acid 240 ablates the binding of the mAb OKT4. A positively charged amino acid residue at this position is found in chimpanzee, rhesus macaque, mouse and rat CD4 suggesting that this mutation may confer unique functional properties to the CD4OKT4- protein.

Alleles↗
PubMed1991

Human immunodeficiency virus type-1 infection of homosexual men is accompanied by a decrease in circulating B cells.

As part of the multidisciplinary effort to characterize the natural history of human immunodeficiency virus type 1 (HIV-1) infection, the cell-surface phenotypes of lymphocytes from a cohort of homosexual men were analyzed in detail and related to clinical and laboratory parameters associated with HIV-1 infection. The present study represents a cross-sectional analysis of coded specimens from 153 homosexual men, of whom 74 were seronegative and 79 seropositive for HIV-1. Fewer circulating B lymphocytes (CD19+) were found in HIV-1-seropositive subjects relative to a seronegative reference group. HIV seropositivity was not associated with decreased numbers of CD8+ T cells or activated T cells, which suggests that the number of circulating B cells specifically decreased. In addition to CD19, B cells were measured by CD20 and CD21 in a subset of subjects, and decreases in circulating CD20+ and CD21+ B cells were also apparent in HIV-1-seropositive subjects. The decrease in B-cell numbers was present at the earliest stages of HIV-1 infection (asymptomatic, clinically silent) and became more pronounced at more advanced stages of HIV-1 infection. The absolute B-cell numbers correlated with absolute CD4+ cell numbers (r = 0.59, p less than 0.001). These data suggest that HIV-1 infection is associated with progressive, selective decreases in the numbers of circulating CD4+ T cells and B cells.

Antigens, CD↗
PubMed1990

Recombinant, truncated CD4 molecule (rT4) binds IgG.

CD4 is a cell surface glycoprotein that identifies the subset of human T lymphocytes that induces sIg+ B lymphocytes to differentiate and secrete Ig after intimate T-B cell contact. In the course of studying a recombinant, truncated form of CD4 (rT4) we noticed that goat antibodies of apparently irrelevant specificities bound to immobilized rT4. To directly study whether rT4 interacts with Ig molecules, purified human IgG was added to rT4-coated wells and a dose-dependent interaction between IgG and rT4 was observed by ELISA. Purified myeloma IgG proteins bound to immobilized rT4 with the same avidity as polyclonal IgG that suggests that rT4-IgG binding was not due to the presence of anti-rT4 antibodies in the IgG fraction. IgG from 6 sera bound to rT4 in concentration dependent manner similar to purified IgG. Immobilized rT4 specifically bound IgG, and not IgM, IgA, IgD, or beta 2-microglobulin. The specific interaction of rT4 and IgG was also observed when IgG or IgM were immobilized, demonstrating that IgG binding was not a unique property of immobilized rT4. As with low affinity receptors for IgG, rT4 bound heat aggregated IgG with increased avidity. Neither anti-CD4 mAb nor dextran sulfate inhibited rT4-IgG binding. rT4 bound Fc but not F(ab)2 fragments. Each of the purified IgG subclasses; IgG1, 2, 3, and 4 bound to rT4 with similar avidity. Taken together, these data suggest that rT4 specifically interacts with a public structure on IgG Fc.

Antibodies, Monoclonal↗
PubMed1989

Dextran sulfate and heparin interact with CD4 molecules to inhibit the binding of coat protein (gp120) of HIV.

Dextran sulfate, heparin, and certain other sulfated polysaccharides potently inhibit the adsorption of HIV to CD4+ cells. The mechanism of this inhibition is unclear and, specifically, it is unknown if these agents act at the level of CD4-gp120 binding. For example, previous reports have demonstrated that dextran sulfate does not inhibit the cell surface binding of anti-CD4 mAb known to be directed at the gp120 binding site. In order to confirm and extend these observations, in the present study, it was shown that dextran sulfate does not inhibit the binding of OKT4A, OKT4C, Leu3a, or B66.6 to CD4+ cells as measured by cytofluorography. Next, recombinant forms of CD4 (rT4) and gp120 (rgp120) were utilized to directly study their molecular interaction in the absence of other viral or cellular structures. Reciprocal solid phase ELISA assays were developed to study directly the effects of sulfated polysaccharides on the binding of rT4 to immobilized rgp120 and vice versa. Dextran sulfate, heparin, and fucoidan, but not chondroitin sulfate, inhibited the binding of rgp120 to rT4. Importantly, dextran sulfate and heparin pre-treatment of immobilized rT4, but not immobilized rgp120, inhibited rT4-rgp120 binding. Taken together, these data suggest that while both sulfated polysaccharides and anti-CD4 mAb inhibit gp120 binding, the sulfated polysaccharides interact with sites on CD4 that are distinct from those with which the antibodies bind.

Adjuvants, Immunologic↗
PubMed1989

Haptic integration of object properties: texture, hardness, and planar contour.

Planar objects varying in shape, texture, and hardness were classified under haptic exploration. Classes were defined by values on one dimension, or redundantly, by two or three dimensions. Response times and exploratory procedures (Lederman & Klatzky, 1987) were recorded. Experiment 1 showed that a second dimension speeded responses for all combinations (redundancy gain), but a third dimension produced no further effect. In Experiments 2 and 3, classification trials began with two redundant dimensions, and subsequently one was withdrawn (held constant). When texture and hardness varied redundantly, withdrawal of either increased response time--even when subjects were initially instructed to focus on one dimension. Joint exploration for texture and hardness dominated whenever the two varied redundantly and persisted despite withdrawal. Redundancy gains (Experiment 1), but not substantial withdrawal effects (Experiments 2 and 3), were observed for combinations of texture or hardness with planar contour, indicating less integration than between substance dimensions. Compatibility of exploratory procedures appears to constrain dimensional integration.

Attention↗
PubMed1984

Ventricular fibrillation following canine coronary artery reperfusion: different outcomes with pentobarbital and alpha-chloralose.

We compared the incidence of ventricular fibrillation after release of a 20 min-proximal left anterior descending coronary artery ligation in dogs anesthetized with either pentobarbital (N = 26) or morphine sulfate plus alpha-chloralose (N = 26). Results were analyzed using the logistic risk regression model. In each group, outcome correlated with the amount of myocardium perfused by the ligated vessel (myocardium "at risk") as measured by postmortem coronary injection of monastral dyes. At any given myocardium at risk, animals anesthetized with alpha-chloralose were less likely to fibrillate after release than those anesthetized with pentobarbital (p less than 0.01). This difference in outcome can be described by the myocardium at risk at which half the animals are expected to fibrillate (MAR50). MAR50 was 20.9 g for the pentobarbital group and 30.7 g for the alpha-chloralose group. Myocardium at risk should be taken into account in intervention studies using this coronary reperfusion arrhythmia model. We chose the logistic risk regression model to correct for this variable because it allowed a good fit of the data and offered a concise standard format for expressing the results. Outcome in reperfusion studies may be influenced by the choice of anesthetic agent.

Anesthesia↗
PubMed1984

A method for quantitating antifibrillatory effects of drugs after coronary reperfusion in dogs: improved outcome with bretylium.

We developed a quantitative approach to assess the antifibrillatory effects of short-term interventions in a canine preparation of ventricular fibrillation caused by coronary reperfusion, and applied it to evaluate the antifibrillatory effects of bretylium tosylate. Twenty-five dogs were given 10 mg/kg infusions of bretylium over 10 min, subjected to a 20 min proximal left anterior descending coronary artery ligation followed by sudden release, and compared with 25 animals given saline placebo. Drug infusion was begun 90 min before reperfusion to avoid evaluation of outcome during the phase of drug-induced catecholamine release and to allow adequate time for bretylium uptake in the myocardium. The relationship between the likelihood of ventricular fibrillation during reperfusion and the amount of myocardium perfused by the occluded vessel (myocardium at risk) was analyzed with the logistic risk-regression model. This model was developed to control for the effects of amount of myocardium at risk on outcome. For both the bretylium and the placebo groups the incidence of ventricular fibrillation correlated significantly with amount of myocardium at risk. However, animals treated with bretylium had an improved outcome for a given amount of myocardium at risk. In other words, the curve relating outcome to myocardium at risk was shifted significantly to the right. The amount of myocardium at risk required for half the placebo-treated animals to fibrillate was 20.3 g and that required for half the bretylium-treated animals to fibrillate was 27.9 g, or 37% more than that for the placebo group. This logistic risk-regression analysis format permits quantification of treatment effects while accounting for variability in amount of myocardium at risk.

Animals↗
PubMed1984

Nonreactive contraction stress test: clinical significance.

Between September 1, 1976, and December 31, 1980, there were 4629 contraction stress tests performed at Women's Hospital, Memorial Hospital Medical Center of Long Beach, California. Forty-four (1.0%) of these tests were completely nonreactive. Eight of 3367 negative contraction stress tests (0.2%), 19 of 1124 equivocal contraction stress tests (1.7%), and 17 of 63 positive contraction stress tests (27.0%) were nonreactive. When compared with patients who had reactive tests, only those patients with a nonreactive, positive contraction stress test had significantly increased perinatal mortality and infants with low Apgar scores. Twelve percent of patients with nonreactive contraction stress tests had fetuses with congenital anomalies. Eighteen percent of patients with nonreactive tests were taking phenobarbital or other sedative drugs, and 45% of patients with nonreactive tests were hypertensive. Excluding anomalous fetuses, there were no perinatal deaths and no Apgar scores below 7 at five minutes in patients with nonreactive negative, or nonreactive equivocal, contraction stress tests as the worst test result. The hypothesis that the completely nonreactive negative contraction stress test as the worst test result is associated with increased perinatal mortality and morbidity could not be substantiated. Standardization of criteria for reactivity and interpretation of the contraction stress test using the entire testing period is desirable.

Apgar Score↗
PubMed1983

Neonatal paracetamol poisoning: treatment by exchange transfusion.

The metabolism and excretion of paracetamol was studied in an infant of 29 weeks' gestation who was exposed to the drug when his mother ingested 32.5 g 16 hours before delivery. We have confirmed that sulphation is the major pathway and that the mixed function oxidase system is sufficiently active at this gestational age to produce hepatotoxic metabolic products. As most of the recognised drug treatments for paracetamol poisoning seemed unsuitable in this case, the infant was treated with exchange transfusions.

Acetaminophen↗
PubMed1983

Biological functions of T-cell surface glycoproteins.

The OKT4 monoclonal antibody reacts with a 62 KD cell surface glycoprotein present on a subset of human T cells with the capacity to help or induce B-cell differentiation. The OKT8 monoclonal antibody reacts with a 76 KD cell surface glycoprotein present on a subset of human T cells with the capacity to suppress B-cell differentiation. The current studies were undertaken to determine whether the T4 and/or T8 antigens themselves play any role in the helper or suppressor function mediated by OKT4+ or OKT8+ cells. Specifically, we asked if monoclonal antibodies that react with noncompeting epitopes on the T4 or T8 molecules could block helper or suppressor function. Isolated human B cells were triggered in vitro to differentiate into antibody-forming cells (AFC) by autologous OKT4+ cells and macrophages in the presence or absence of OKT4 antibodies. By means of a reverse hemolytic plaque assay, AFC were detected as plaque-forming cells (PFC). We found that OKT4A, but not OKT4, antibody inhibited the PFC response over a wide range of concentrations. The antibodies OKT4B, OKT4C, OKT4D, OKT4E inhibited the PFC response to varying degrees. Importantly, inhibition by OKT4A occurred only if the antibody was present during the first 24 hours of cell culture. In the second set of experiments, OKT8+ cells were added to cultures containing B cells, and OKT4+ cells in the presence or absence of OKT8 antibodies, PFC activity was measured 7 days later. We found that the addition of OKT8E or OKT8G, but not OKT8B, OKT8C, OKT8D, OKT8F, or OKT8H, antibodies significantly inhibits the suppressor function mediated by OKT8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1979

Myocardial infarct imaging with 99mTc-pyrophosphate and 99mTc-methylene diphosphonate: lack of correlation.

A prospective study of eight patients with recent transmural myocardial infarction was performed using 99mTc-Sn-pyrophosphate and 99mTc-Sn-methylene diphosphonate in each patient. All pyrophosphate scans were strongly positive whereas the diphosphonate scan was strongly positive in only one case. We conclude that 99mTc-Sn-pyrophosphate is preferable to 99mTc-Sn-methylene diphosphonate for myocardial imaging.

Diphosphates↗
PubMedDate not supplied

TRAF-3 interacts with p62 nucleoporin, a component of the nuclear pore central plug that binds classical NLS-containing import complexes.

The TRAF-3 gene encodes a number of splice-variant isoforms that function as adapter molecules in NF-kappaB signaling, in part by associating with the cytoplasmic tails of CD40 or other TNF-receptor (TNF-R) family members. To identify downstream molecules in TRAF-3 signaling, a yeast two-hybrid library was screened with a full-length TRAF-3 construct. Nine independent TRAF-3 interacting clones encoded fragments of p62 Nucleoporin (p62), a 522 amino acid (aa) component of the nuclear pore central plug, that is known to bind karyopherin-beta/classical-NLS import factor complexes. The interaction of p62 with TRAF-3 was specific, since p62 failed to interact with TRAF-2, -4, -5, or -6. Deletional analysis in yeast revealed that the p62:TRAF-3 interaction is mediated by a p62 carboxy (C)-terminal coiled-coil domain and TRAF-3's fifth zinc (Zn) finger and coiled-coil domain. In human 293 T cells, recombinant TRAF-3 or p62 specifically co-immunoprecipitates the other species. In addition, endogenous p62 co-precipitates over-expressed TRAF-3. The functional effects of over-expressing a TRAF-3 binding fragment, p62(aa 336-522) were studied on NF-kappaB-dependent, or control STAT1-dependent reporter activity in 293 T cells, either resting or after stimulation by CD40 or IFN-gamma, respectively. Over-expression of p62(aa 336-522) induces NF-kappaB activation in resting cells and augments CD40-induced NF-kappaB activation, but has no effect on control STAT1 reporter activity, either at baseline or after IFN-gamma induction. The finding that TRAF-3 binds p62, suggests that TRAF-3 may serve as an adapter molecule at the nuclear membrane, in addition to its known adapter function at the plasma membrane.

CD40 Antigens↗