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Biomedical subjects

J A Edwards

Publications and source records attributed to J A Edwards.

At least 19 recordsLinked to original sources
PubMed1992

Quantitative comparison of radiolabeled antibody therapy and external beam radiotherapy in the treatment of human glioma xenografts.

Using 90Yttrium radiolabeled antibodies, radioimmunotherapy was compared to fractionated external beam radiotherapy in the treatment of human glioma xenografts. Antibody treatments required administration of an approximately threefold greater total dose compared to external beam treatments to achieve the same tumor regrowth delay. Following multi-fraction external beam radiation treatments, tumor regrowth delay demonstrated a large fractionation effect (alpha/beta = 2.3 Gy, 95% confidence limits 0.4-4.2 Gy), suggesting that much of the ineffectiveness of the antibody treatments could be caused by a large dose-rate effect in this system. Despite the large fractionation effect, the regrowth delay was small for a large single-fraction external beam irradiation, possibly because of tumor hypoxia. When compared to external beam radiation, radiolabeled antibody treatments resulted in a comparatively diminished tumor bed effect, suggesting radioimmunotherapy spares normal tissue surrounding the tumor.

Animals↗
PubMed1992

Computer methods in child language research: four principles for the use of archived data.

With the increasing use of computers in language research, there is a need for caution concerning several new issues of data accountability. This paper presents four principles for archive-based language research: Maximum Readability and Minimum Bias; Consistent Encoding for exhaustive computer search; Systematic Contrastiveness; and Data Comparability in elicitation, transcription and coding. These and related principles are illustrated by examples from existing computer archives, and strategies are suggested for minimizing detrimental effects of violations. Finally, the paper describes some implications of the principles for properties of a field-wide and international standard of transcription of language data.

Archives↗
PubMed1992

Variation in a medical faculty's decisions to transfuse. Implications for modifying blood product utilization.

Previous studies have identified disconcerting differences in transfusion practices among physicians. This article investigates decisionmaking on transfusion by a medical school faculty. One hundred fourteen physicians indicated their propensity to transfuse 24 hypothetical patients who varied systematically in four clinical cues. Physicians agreed with transfusion for a widely divergent number of these patients (mean, 14.6; standard deviation, 5.5; range, 0 to 24). Although the physicians agreed on the order of importance of the clinical cues, they varied significantly in the importance they empirically attributed to the cues and in their thresholds for transfusion. Aside from a slightly higher propensity to transfuse by general internists, differences in decisionmaking were not attributable to physician-based variables. The wide variability in decisionmaking among physicians in the face of agreement on the order of importance of clinical cues suggests that quality assurance programs, and guidelines that only list the cues that ought to influence transfusion decisions, have low potential to achieve blood-product conservation.

Anemia↗
PubMed1992

Fibrin degradation by rat pulmonary alveolar epithelial cells.

The persistence of intra-alveolar fibrin during acute and chronic inflammatory lung diseases indicates that the normally profibrinolytic environment of the alveolar space has been altered as part of the disease process. We have recently shown that alveolar epithelial cells may control fibrinolysis by expressing both urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1. In this study, monolayers of rat alveolar epithelial cells were used as a model of the alveolar surface and were found to lyse plasma-derived fibrin matrices by a process that was plasminogen and uPA dependent. Fibrinolysis was not achieved by fluid-phase epithelial products but required the presence of epithelial cells, optimally in close contact with the clot surface. Epithelial cell-mediated fibrinolytic activity was augmented 99% by endotoxin and suppressed 66% by dexamethasone. Fibrinolysis also increased 84% as cells aged in culture from day 1 to day 4, during which time the cells lose many type II cell characteristics and assume a type I cell-like phenotype. We conclude that alveolar epithelial cells actively participate in fibrin clearance through mechanisms that require close proximity between epithelial cell and clot surfaces. Alterations in these mechanisms may be partly responsible for the persistence of intraalveolar fibrin during lung inflammation.

Amiloride↗
PubMed1991

Endocrine, neural, and immune control of secretory component output by lacrimal gland acinar cells.

Androgens regulate the synthesis and secretion of secretory component (SC), the IgA antibody receptor, by acinar cells from the lacrimal gland. However, this hormone action may be susceptible to significant modification by other agents from the endocrine, nervous, or immune systems. To investigate the nature of this neuroimmunoendocrine interaction, the present study examined the impact of hormones, neurotransmitters, and lymphokines on basal and androgen-induced SC production by lacrimal gland acinar cells in vitro. Our results demonstrated that vasoactive intestinal peptide, the beta-adrenergic agonist, isoproterenol, PGE2, IL-1 alpha, IL-1 beta, and TNF-alpha significantly increased media SC levels in control or androgen-containing cell cultures. In contrast, the cholinergic agonist, carbachol, significantly decreased cellular SC output. These effects may be mediated through the agents' known capacity to alter intracellular cAMP levels. In support of this hypothesis, exposure of acinar cells to stimulators or analogues of cAMP resulted in a significant enhancement of SC production. Thus, these findings indicate that SC output in lacrimal tissue may be modulated by interactions between the endocrine, nervous and immune systems.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Injury of rat pulmonary alveolar epithelial cells by H2O2: dependence on phenotype and catalase.

In a variety of inflammatory lung diseases, type I alveolar epithelial cells are more likely to be injured than are type II cells. Because oxidants have been implicated as a cause of injury in various inflammatory lung diseases, we evaluated the effects of differentiation on alveolar epithelial cell susceptibility to H2O2-induced injury. With the use of isolated rat type II cells in culture, we found that the cytotoxic effect of H2O2 increased between days 2 and 7, when type II cells are known to lose their distinctive type II properties and assume a more type I-like appearance. We previously reported that type II cells utilized both intracellular catalase and glutathione-dependent reactions to protect against H2O2. We therefore examined whether alterations in either of these protective mechanisms were responsible for the differentiation-dependent changes in sensitivity to H2O2. We found that catalase activity within alveolar epithelial cells decreased between 2 and 7 days in culture, whereas no changes were detected in glutathione-dependent systems. We then used a histochemical technique that detects catalase activity and found that type II cells within rat lungs possessed numerous catalase-containing peroxisomes, whereas very few were detected in type I cells. These findings demonstrate that as type II cells assume a type I-like phenotype, they become more susceptible to H2O2-induced injury. This increased susceptibility is associated with reductions in intracellular catalase activity, both in vitro and in vivo.

Animals↗
PubMed1990

Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies.

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5 or ZME018. Tumor regression was measured in 1 of 12, 9 of 10, and 12 of 12 compared to 0 of 10, 1 of 10, and 2 of 10 animals following administration of 50, 100, or 200 microCi 90Y-labeled P96.5 and ZME018, respectively. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3% 28 and 58 days following 100 and 200 microCi 90Y-radiolabeled P96.5 administration, respectively. In contrast, no average decrease in tumor volume was noted following 50, 100, or 200 microCi 90Y-labeled ZME018.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Targeting and therapy of human glioma xenografts in vivo using radiolabeled antibodies.

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (uCi) of tumor activity per gram per 100 uCi injected activity compared to 4.5 uCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. Tumor dose found in normal organs is less than 20% of the tumor dose, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibodies QCI054 and ZME018, which define a tumor-associated and a second melanoma-associated antigen, respectively, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5, QCI054, and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Average absorbed doses of 3770 +/- 445 (mean +/- SEM), 2043 +/- 134, and 645 +/- 48 cGy in tumor, 353 +/- 41, 243 +/- 22, and 222 +/- 13 cGy in a contralateral control intramuscular site, 980 +/- 127, 815 +/- 41, and 651 +/- 63 cGy in liver, and 275 +/- 14, 263 +/- 11, and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 uCi 90Y-radiolabeled P96.5, QCI054, and ZME018, respectively. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5, QCI054, or ZME018. Striking tumor regression and prolonged survival were measured following administration of 90Y-labeled P96.5. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3 percent 28 and 58 days following 100 and 200 uCi 90Y-radiolabeled P96.5 administration, respectively. The time required to achieve four times the initial tumor volume was 6.1 +/- 0.9 days for buffer; 43 +/- 12 and 63 +/- 10 days for 50 and 100 uCi 90Y-radiolabeled P96.5; 7 +/- 2, 20 +/- 1, and 53 +/- 4 for 50, 100, and 200 uCi 90Y-radiolabeled QCI054; and 9 +/- 1, 13 +/- 1, and 29 +/- 3 days for 50, 100, and 200 uCi 90Y-radiolabeled ZME018, respectively. Average tumor regrowth failed to occur 180 days following administration of 200 uCi 90Y-labeled P96.5.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Toxicity studies with quinine hydrochloride.

Three-month studies in the rat, a rat embryo-toxicity study and a specific study to investigate ototoxicity were carried out with quinine hydrochloride. The results of these studies suggest an acceptable daily intake of 40 mg quinine hydrochloride for an adult. There were no indications of teratogenic effects and no indications of interference with auditory function in rats receiving up to 200 mg/kg.

Animals↗
PubMed1987

Synthesis and gastric antisecretory properties of allenic 16-phenoxy-omega-tetranor prostaglandin E analogs.

In order to improve the modest oral activity of PGE2 as an inhibitor of gastric acid secretion, analogs were prepared and tested orally in histamine-challenged rats. Insertion of a double bond at C-4, resulting in the 4,5-allene analog of PGE1, gave a small increase in activity. Introduction of the omega-tetranor-16-phenoxy lower sidechain, a modification known to enhance activity in the PGF series, gave an eight-fold increase in activity. The analog having both modifications (enprostil, 2) showed a six hundred-fold increase in oral antisecretory activity over PGE2, which may reflect a potentiation effect. Modification of enprostil at C-1 (various esters) and at C-11 (11-methyl, 11-deoxy) generally resulted in compounds of high activity while modifications at other sites generally resulted in significant reductions in activity.

Animals↗
PubMed1987

Monozygotic female twin carriers discordant for the clinical manifestations of Duchenne muscular dystrophy.

We studied twin sisters, in their sixth decade, who were obligate carriers of Duchenne dystrophy. One had a slowly progressing limb-girdle myopathy since her mid-20s. The other sister showed no evidence of neuromuscular disease by history or on physical examination but had high serum CK values and degeneration and regeneration of fibers in a muscle biopsy. Otherwise, they were phenotypically identical, karyotypically normal females with cytogenetically normal X-chromosomes. Based on red cell and HLA loci antigen determinations, there was a 99.2% probability that they were monozygotic. The mutant gene segregating in the family is probably linked to the Xp21 DNA marker pERT87.

Diseases in Twins↗
PubMed1987

Diminished acquisition of iron by reticulocytes from mice with hemoglobin deficit.

Reticulocyte iron and transferrin uptake was studied in hemoglobin deficit (gene symbol, hbd), an autosomal recessive trait in the mouse characterized by hypochromic microcytic anemia, reticulocytosis, hyperferremia, and increased red-cell-free protoporphyrin. Reticulocyte-rich red cells were incubated in vitro in a mixture of 125I-labeled diferric mouse transferrin and 59Fe-labeled iron-saturated mouse plasma. At 37 degrees C, the uptake of transferrin by reticulocytes from affected animals (15 ng/micrograms RNA) was the same as that of reticulocytes from control animals. However, the uptake of iron by affected reticulocytes (0.11 ng/micrograms RNA) was significantly lower than that by control reticulocytes (0.24). At 4 degrees C, transferrin binding by affected and control reticulocytes was again indistinguishable. The deficiency in the uptake of iron by affected reticulocytes was not observed on incubation at 4 degrees C. Scatchard analysis of transferrin receptors on hbd/hbd and control reticulocytes showed no difference in pKD and a slight elevation in number of receptors per reticulocyte for hbd/hbd animals. These findings suggest that hbd/hbd reticulocytes have a defect in iron acquisition that is distal to the binding of transferrin to the cell membrane receptor. This defect is similar to one already described in the anemia of the Belgrade laboratory rat.

Anemia, Hypochromic↗
PubMed1986

Differential expression of HLA class II antigens in fetal human spleen: relationship of HLA-DP, DQ, and DR to immunoglobulin expression.

Frozen sections of human fetal spleen from 12 to 20 wk gestation were examined by using polyclonal antibodies to Ig isotypes, monoclonal antibodies to HLA class II subregion locus products, B and T cells, and follicular dendritic cells. Scattered lymphoid cells in spleen sections from fetuses of 12 to 13 wk gestational age expressed IgM but not IgD. The appearance of lymphoid cells expressing IgD occurred at 14 to 15 wk before the formation of loose clusters of B cells at 16 wk. IgD expression was associated mainly with cells in these clusters, which by 17 wk had become definite follicles. Follicular dendritic cells were not detectable until 20 wk. OKT3-positive T cells were not detected until 17 wk, and at 20 wk constituted 5% of the nucleated cell population. HLA-DR- and DP-positive lymphocytes and macrophages were detectable in fetal spleen from 12 wk onward; DR was expressed on more cells than DP, and the numbers of cells stained by HLA-DR-specific monoclonal antibodies exceeded the number of Ig-positive cells in all spleens examined. HLA-DQ was expressed by consistently fewer cells than HLA-DR and -DP in all spleens tested. The small number of DQ-positive cells in spleens from 12- to 13-wk fetuses had the morphology of macrophages; HLA-DQ expression by lymphoid cells followed a similar pattern to IgD expression and was associated mainly with follicular lymphocytes. It could be demonstrated by double-labeling experiments that all follicular IgM-positive cells in 17- to 20-wk spleens expressed HLA-DP, DQ, and DR antigens: IgM-positive cells in 12- to 16-wk spleens and interfollicular IgM-positive cells in 17- to 20-wk spleens all expressed HLA-DR, but only 59% and 43% expressed DP and DQ, respectively. Ninety-one to 100% of IgD-positive cells in all spleens examined expressed HLA-DQ in addition to DR and DP. In these experiments IgD-negative, DQ-positive cells had the morphologic appearance characteristic of macrophages. These data suggest that class II antigens are differentially expressed on developing lymphoid cells; DR and DP expression occurring in the earliest spleens examined, with expression of DP on a subpopulation of DR-positive cells; IgD and DQ expression appears to be coincident on maturing B cells as they begin to form follicles. An immunoregulatory role for HLA-DQ in B cell development is implicated and remains to be fully investigated.

Antibodies, Monoclonal↗
PubMed1986

Adult-onset autosomal dominant limb-girdle muscular dystrophy.

We describe a kindred with a rare autosomal dominant myopathy limited to the limb-girdle muscles, beginning insidiously any time from the late second through the sixth decades and followed by slow progression. Pelvifemoral precedes scapulohumeral weakness, and proximal appendicular involvement antedates limited distal paresis. Expressivity varies and includes an asymptomatic myopathy (preclinical or subclinical) and a nonmanifesting carrier state that extends well into the eighth decade. A variety of nonspecific changes are present in muscle on light, enzyme histochemical, and electron microscopic examination; of these changes, "rimmed" or autophagic vacuoles are the most characteristic. We identified one very similar previously reported genealogy. The similarities between the two unrelated families clearly establish this dystrophic process as a distinct genetic entity; their differences suggest genetic heterogeneity.

Adult↗