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Biomedical subjects

A Davidson

Publications and source records attributed to A Davidson.

At least 127 records · Page 7Linked to original sources
PubMed1992

Immune tolerance to a defined heterologous antigen after intrasplenic hepatocyte transplantation: implications for gene therapy.

Development of a host immune response against gene products expressed by genetically modified cells could be a serious limitation for gene therapy. During examination of whether site-specific differences in antigen presentation could regulate the host immune response, we observed an absence of antibodies against hepatitis B virus surface antigen (HBsAg) when HBsAg producing transgenic hepatocytes were transplanted into the spleen. Intrasplenic transplantation resulted in translocation of a large number of cells into the portal vascular bed and liver sinusoids. In these recipients, HBsAg secreted by the transplanted hepatocytes circulated indefinitely in the blood. In contrast, subcutaneous or intraperitoneal transplantation of the transgenic hepatocytes induced an anti-HBs response, followed by clearance of serum HBsAg. Rechallenge with HBsAg in a highly immunogenic form failed to break the tolerance in intrasplenic hepatocyte recipients even though these animals responded to another antigen (keyhole limpet hemocyanin). Immunization with HBsAg in intraperitoneal recipients of HBsAg producing hepatocytes further elevated anti-HBs titers. Our results indicate that hepatocyte transplantation into the portal vascular bed via injection into the spleen can confer immune tolerance to secreted heterologous antigens. This finding should have important implications for human gene therapy as well as for analyzing the mechanisms of immune tolerance.

Animals↗
PubMed1991

Native Xenopus oocytes express two types of muscarinic receptors.

We have recently described two types of muscarinic responses in native Xenopus oocytes of different donors (common and variant) that display qualitative and quantitative differences (Lupu-Meiri et al., 1990). Here we characterized the muscarinic receptors mediating these two types. The anti-muscarinic toxins from Dentroaspis significantly inhibited responses in oocytes of common donors, but had little effect on responses in oocytes of variant donors, possibly indicating expression of different receptor subtypes. Using specific muscarinic antagonists, we found that oocytes of common donors exhibit a pattern compatible with the M3 subtype of muscarinic receptors, while oocytes of variant donors appear to possess receptors of the M1 subtype. To more directly determine the subtypes of muscarinic receptors in oocytes of both populations of donors, we have microinjected antisense oligonucleotides into native oocytes. Antisense oligonucleotides to unique sequences in the N-terminal and the third cytoplasmic loop of M3 muscarinic receptors caused a significant inhibition of the response of common oocytes, but had virtually no effect on responses in oocytes of variant donors. Conversely, oligonucleotides complementary to the unique sequences of the m1 muscarinic receptors inhibited the response in variant oocytes, but not in oocytes of common donors. We conclude that native Xenopus oocytes of different donors phenotypically express either M3-like (majority) or M1-like (minority) muscarinic receptor subtypes. The differences in receptor subtype expression may explain the different characteristics of responses in the two populations.

Animals↗
PubMed1991

Isolation and characterization of mutations in the bacteriophage lambda terminase genes.

The terminase enzyme of bacteriophage lambda is a hetero-oligomeric protein which catalyzes the site-specific endonucleolytic cleavage of lambda DNA and its packaging into phage proheads; it is composed of the products of the lambda Nul and A genes. We have developed a simple method to select mutations in the terminase genes carried on a high-copy-number plasmid, based on the ability of wild-type terminase to kill recA strains of Escherichia coli. Sixty-three different spontaneous mutations and 13 linker insertion mutations were isolated by this method and analyzed. Extracts of cells transformed by mutant plasmids displayed variable degrees of reduction in the activity of one or both terminase subunits as assayed by in vitro lambda DNA packaging. A method of genetically mapping plasmid-borne mutations in the A gene by measuring their ability to rescue various lambda Aam phages showed that the A mutations were fairly evenly distributed across the gene. Mutant A genes were also subcloned into overproducing plasmid constructs, and it was determined that more than half of them directed the synthesis of normal amounts of full-length A protein. Three of the A gene mutants displayed dramatically reduced in vitro packaging activity only when immature (uncut) lambda DNA was used as the substrate; therefore, these mutations may lie in the endonuclease domain of terminase. Interestingly, the putative endonuclease mutations mapped in two distinct locations in the A gene separated by a least 400 bp.

Bacteriophage lambda↗
PubMed1991

Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype.

This study describes a methodology for generating stable, cloned, EBV-transformed IgG- and IgM-producing human B cell lines. Using these lines we have characterized immunoglobulin V gene utilization in an anti-DNA-associated idiotypic system. The 31 anti-DNA-associated idiotype is encoded preferentially by the VK1 gene family, and, in all probability, reflects a germ line gene-encoded framework determinant. Analysis of these lines indicates that the DNA-binding antibodies produced by B cell lines from SLE patients may differ from DNA binding myeloma proteins and from natural autoantibodies.

Antibodies, Antinuclear↗
PubMed1991

Endocrine and biological factors influencing implantation of human embryos following cryopreservation.

Several parameters affecting survival and implantation of frozen-thawed embryos were studied. Of 386 embryos frozen in dimethylsulfoxide (DMSO) or in 1,2 propanediol (PROH), the survival rate was 63.5% (245/386). Three different methods of cycle preparation were compared prior to thawed embryo replacement. The pregnancy rate was 16.1% (9/56) in spontaneous cycles; 11.4% (5/44) in an ovarian stimulation protocol; and 9.5% (4/42) with estrogen and progesterone substitutional therapy (p = NS). There was no difference in the estradiol/progesterone ratio among the three different protocols during the early luteal phase of the cycle, which may indicate that implantation of thawed embryos could be related to their developmental potential rather than to the endometrial environment. In the spontaneous cycles, when endometrium was synchronized or advanced to embryonic stage up to 32h, implantation rate was 29.2%.

Adult↗
PubMed1990

Cardiomegaly--what does it mean? A comparison of echocardiographic to radiological cardiac dimensions in children.

Several cardiac dimensions were estimated by echocardiography and plain chest films in 36 healthy children and 85 children with heart disease. Left and right ventricular volumes and left ventricular mass were estimated by echocardiography, and compared with the cardiothoracic ratio, cardiac frontal area, and total cardiac volume, estimated from x-rays films. In healthy children there was poor correlation between the radiological and echocardiographic estimates. In children with heart disease, there was a close correlation of radiographic total cardiac volume with echocardiographic left ventricular volume and mass, and combined ventricular volumes. Cardiothoracic ratio and cardiac frontal area did not correlate with echocardiographic data. For a more reliable evaluation of the heart size, in children as in adults, the total cardiac volume has to be calculated from both the frontal and lateral films, as estimates obtained from only a frontal film are unreliable.

Adolescent↗
PubMed1990

A scoring system for induction of labor using prostaglandin E2 vaginal tablets.

A randomized controlled trial was carried out in order to establish the efficacy of a scoring system for calculating the dose of vaginal prostaglandin E2 tablets for the induction of labor. One hundred ten women were included in the study. The patients received a dose of prostaglandin E2 calculated according to a scoring system based on the Bishop's score, or the standard dose of 3 mg repeated 6 h later if labor did not start. The percentage of inductions achieved was the same with both regimens (92.7%). The mean total dose used in the scoring system-group (2.7 mg) was significantly lower than that used in the 3-mg group (3.5 mg, P less than 0.025). Thirty-seven of 55 women receiving the scoring dose delivered with amounts of 2.5 mg prostaglandin E2 or less. Three cases of uterine hyperstimulation were observed in the 3-mg group whereas no cases were observed in the scoring group. The scoring system is proposed as a method for calculating the dose of vaginal prostaglandin E2 for induction of labor and minimizing the risk of overdosage.

Administration, Intravaginal↗
PubMed1990

Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction.

Neutrophils, a source of proteolytic enzymes and oxygen free radicals, have been shown to participate in animal models of myocardial ischemic injury. To characterize neutrophil activation in human ischemic heart disease, a specific neutrophil elastase-derived fibrinopeptide in plasma was measured in 25 patients with stable angina pectoris, 29 patients with unstable angina pectoris, 17 patients with acute myocardial infarction and 22 control subjects. Mean plasma levels (+/- standard error) of a neutrophil elastase-derived fibrinopeptide (B beta 30-43) measured by a specific radioimmunoassay were fivefold higher in patients with acute myocardial infarction (877 +/- 337 pmol/liter, p less than 0.02) and 13-fold higher in patients with unstable angina (2,277 +/- 613 pmol/liter, p less than 0.006) as compared with control subjects (172 +/- 74 pmol/liter). Mean plasma levels of peptide B beta 30-43 in patients with stable angina (676 +/- 334 pmol/liter), although higher than in control subjects, were not significantly increased (p = 0.64). Total leukocyte counts were 11.0 +/- 0.6 x 10(6)/ml in those with acute myocardial infarction, 9.2 +/- 0.7 x 10(6)/ml in those with unstable angina, 7.1 +/- 0.3 x 10(6)/ml in those with stable angina and 7.7 +/- 0.4 x 10(6)/ml in control subjects. Although total leukocyte counts in patients with unstable angina pectoris and acute myocardial infarction were higher (p less than 0.01) than in patients with stable angina or in control subjects, elevations in peptide B beta 30-43 levels were independent of the differences in both leukocyte count and absolute neutrophil count as well as in history of smoking, hypertension, diabetes mellitus or treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1990

Preventability of malpractice claims in emergency medicine: a closed claims study.

We conducted a retrospective study of 262 malpractice claims against emergency physicians insured in Massachusetts by the state-mandated insurance carrier; these 262 claims were closed in the years 1980 through 1987. A total of $11,800,156 in indemnity and expenses was spent for these 262 claims. In 211 cases, the allegation was failure to diagnose a medical or surgical problem. One hundred eighty-four of these cases were included in the following eight diagnostic categories: chest pain, abdominal pain, wounds, fractures, pediatric fever/meningitis, aortic aneurysm, central nervous system bleeding, and epiglottitis. These eight categories accounted for 66.44% of the total dollars spent for the 262 claims. Because of the high incidence and dollar losses attached to these eight diagnostic categories, the Massachusetts Chapter of the American College of Emergency Physicians (MACEP) has developed clinical guidelines for the evaluation of these high-risk areas. Of the 184 high-risk claims, 99 claim files were reviewed; 45 of these reviewed claims were judged by physician reviewers as preventable by the application of the MACEP high risk clinical guidelines. From 22.26% to 46.4% of the $11,800,156 spent on the 262 claims could have been saved by the application of the MACEP clinical guidelines.

Chest Pain↗
PubMed1990

Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes.

We report the molecular characterization of 2A4, an IgG, DNA-binding antibody bearing the 3I and F4 idiotypes which are associated with anti-DNA antibodies in serum of patients with systemic lupus erythematosus (SLE). The antibody is produced by an EBV-transformed B cell line derived from a patient with multiple myeloma whose myeloma protein is also an IgG, 3I-reactive, F4-reactive, DNA-binding immunoglobulin, although the 2A4 antibody does not itself represent the myeloma protein. The 2A4 heavy chain is encoded by a VH4 gene, a D-D gene fusion and the JH6 gene; the light chain is derived from a Vk1 gene and the Jk2 gene. This is the first human antibody shown to have a CDR3 encoded by a D-D fusion. DNA sequence analysis of the 2A4 VH gene together with a Southern blot of genomic DNA probed with a 2A4 VH-specific oligonucleotide strongly suggest it to be somatically mutated. The data provide evidence that human autoantibodies can be products of somatically mutated genes and suggest that the 2A4 antibody may reflect the selective pressure of antigen.

Amino Acid Sequence↗
PubMed1990

Enhancement of hypoxemia by atrial shunting in cystic fibrosis.

Patients with CF may develop hypoxemia which seems disproportionate to the degree of pulmonary disease. In a series of patients with CF and advanced pulmonary disease undergoing transesophageal echocardiography for the evaluation of cor pulmonale, eight of 15 patients were found to have atrial shunts through a stretched foramen ovale. To our knowledge, this is the first observation of intracardiac shunting in CF. This phenomenon may account for unexplained levels of cyanosis and worsening of hypoxemia with exercise, vasodilators, or PEEP and poses the threat of paradoxic emboli when central venous lines are used in these patients.

Adult↗