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Biomedical subjects

E A Smith

Publications and source records attributed to E A Smith.

At least 19 recordsLinked to original sources
PubMed1992

Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies.

OBJECTIVES: The aims of this study were to better characterize valve disease in systemic lupus erythematosus and to determine its association with antiphospholipid antibodies. BACKGROUND: Estimates of the prevalence of valve disease in systemic lupus erythematosus have been higher in autopsy series than in clinical studies using transthoracic echocardiography. Antiphospholipid antibodies have been suggested to be a primary pathogenetic factor. METHODS: Transesophageal echocardiography was performed on 1) 54 patients with lupus erythematosus, 22 of them with (group I) and 32 without (group II) antiphospholipid antibody; 2) on 10 patients with antiphospholipid syndrome (group III); and 3) on 35 normal subjects (group IV). RESULTS: Patients in groups I and III had similar types and concentrations of antibodies. Leaflet thickening was found in 50% of group I, 47% of group II, 10% of group III and 9% of group IV patients (group I or II vs. group III or IV, p < 0.03). Leaflet thickening in patients with lupus erythematosus was diffuse; it usually involved the mitral and aortic valves and was associated with valve regurgitation (73%) or valve masses (50%). Valve masses were observed in 41% of group I, 25% of group II, 10% of group III and in none of group IV patients (group I or II vs. group IV, p < 0.002). Most valve masses in patients with lupus erythematosus were located near the base on the atrial side of the mitral valve or on the vessel side of the aortic valve, had variable size (0.2 to 0.85 cm2), shape and echodensity. Valve regurgitation was observed in 64% of group I, 59% of group II, 10% of group III and 20% of group IV patients (group I or II vs. group III or IV, p < 0.006). Moderate or severe regurgitant lesions were noted in 27% of group I and 25% of group II patients. CONCLUSIONS: Lupus erythematosus valve disease is frequent (74%) regardless of the presence or absence of antiphospholipid antibodies. Therefore antiphospholipid antibodies may not be a primary pathogenetic factor. The characteristic appearance of leaflet thickening and masses in patients with lupus erythematosus may be unique.

Adult↗
PubMed1992

Direct demonstration of transcriptional activation of collagen gene expression in systemic sclerosis fibroblasts: insensitivity to TGF beta 1 stimulation.

Lesional fibroblasts propagated from the skin of patients with scleroderma, when compared to normal fibroblasts, show increased synthesis of several collagens and increased levels of their corresponding mRNAs. Using constructs (COL1A2/CAT) containing the promoter for the alpha 2 (I) collagen gene in transient transfection assays with matched pairs of scleroderma and normal skin fibroblasts, we observed higher transcriptional activity of the COL1A2 gene in scleroderma fibroblasts and, in contrast to normal fibroblasts, no further expression was observed in the presence of TGF beta 1. Analysis of the expression of COL1A2 promoter deletion constructs indicates that the TGF beta responsive element functional in normal fibroblasts and the sequence involved in intrinsic upregulation of COL1A2 gene expression in scleroderma fibroblasts are both located between bp-376 (Bgl II) and bp-108 (Sma I) sites. These data may indicate that intrinsic upregulation of extracellular matrix genes in scleroderma fibroblasts utilizes a TGF beta dependent pathway.

Base Sequence↗
PubMed1992

Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts.

Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.

Adult↗
PubMed1992

Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome.

OBJECTIVE: To investigate the metabolism of L-tryptophan (LT) via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome (EMS). METHODS: Measurement of LT, L-kynurenine, and quinolinic acid in plasma and cerebrospinal fluid (CSF) from subjects with EMS, from asymptomatic users of LT, and from normal subjects. RESULTS: Plasma LT concentrations were lower in untreated EMS patients (n = 5) than in corticosteroid-treated EMS patients (n = 5; P less than 0.05) and in asymptomatic users of LT (n = 5; P less than 0.05). Untreated EMS patients, who had discontinued LT weeks to months prior to study, had significantly higher plasma levels of L-kynurenine and quinolinic acid than did corticosteroid-treated EMS patients (P less than 0.05), normal subjects (P less than 0.02), and asymptomatic users of LT (P less than 0.05). EMS patients also had significantly elevated levels of L-kynurenine (P less than 0.05) and quinolinic acid (P less than 0.001) in CSF compared with normal subjects. After a 1-gm oral dose of LT, untreated EMS patients (n = 4) showed lower peak levels of LT and accentuated synthesis of L-kynurenine and quinolinic acid, compared with these values in corticosteroid-treated EMS patients (n = 2), who responded like normal subjects (n = 5). CONCLUSION: These data demonstrate that during the active phase of EMS, LT metabolism via the kynurenine pathway was accentuated, probably secondary to induction of the enzyme indoleamine-2,3-dioxygenase. Ingestion of large amounts of LT (median daily dose 1.5 gm) resulted in high concentrations of kynurenine-pathway metabolites in blood and extrahepatic tissues, which was accentuated in EMS patients and which may have played a significant role in the pathogenesis of the disease.

Adrenal Cortex Hormones↗
PubMed1992

Assignment of tyrosine-specific T-cell phosphatase to conserved syntenic groups on human chromosome 18 and mouse chromosome 18.

Phosphorylation of proteins on tyrosine is crucially involved in signal transduction and mitogenesis and is regulated by both kinases and phosphatases. Recently, a number of soluble and transmembrane receptor-linked protein tyrosine phosphatases (PTPase) have been characterized. Among these is a 48.4-kDa PTPase encoded by a cDNA isolated from a T-lymphocyte library by low-stringency screening with probes derived from placental PTPase 1B. A human T-cell PTPase (PTPT) cDNA and somatic cell hybrids were used to assign a PTPT gene to conserved syntentic groups on human chromosome 18 and on mouse chromosome 18. Two unlinked sequences, one on human chromosome 1, were also detected.

Animals↗
PubMed1992

Inhibition of PAF-induced activation of human platelets by verapamil.

Verapamil, an inhibitor of calcium channels, was shown to inhibit PAF-induced platelet activation. In the presence of 50 microM Verapamil both thromboxane (Tx) formation and release of ATP from dense granules induced by 100 nM PAF was completely inhibited. This concentration of Verapamil only produced partial inhibition of PAF-induced aggregation. It also reduced the size of the PAF-induced calcium (Ca2+) transient demonstrated in Fura-2 loaded platelets. In the absence of extracellular Ca2+, following chelation by EGTA, PAF was still able to induce a Ca2+ transient confirming the requirement of both intra and extracellular Ca2+ for PAF-induced platelet activation. 100 microM Verapamil was able to completely abolish the calcium transient induced by low doses of PAF. These results further suggest that Verapamil is able to inhibit PAF-induced platelet activation by mechanisms apart from blocking Ca2+ channels.

Adenosine Triphosphate↗
PubMed1992

Differential modulation of bFGF receptors by TGF-beta in adult skin, scleroderma skin, and newborn foreskin fibroblasts.

Effects of transforming growth factor beta (TGF-beta) on proliferative responses to basic fibroblast growth factor (bFGF) were studied in human diploid fibroblasts cell strains derived from three different sources: adult skin, scleroderma, and newborn foreskin. All three types of cell strains were similarly responsive to TGF-beta, whereas adult skin fibroblasts were significantly more responsive to bFGF. Incubation of cells with TGF-beta prior to bFGF addition substantially increased responsiveness of adult skin fibroblasts to this latter cytokine, slightly increased that of scleroderma fibroblasts, and decreased that of foreskin fibroblasts. Modulation of bFGF receptors by TGF-beta correlated positively with these mitogenic effects. Adult skin fibroblasts showed increases of both high- and low-affinity receptors and scleroderma fibroblasts showed small increases of high-affinity receptors only, whereas foreskin fibroblasts showed no changes. Heparitinase treatment of adult skin fibroblasts during TGF-beta pre-incubation resulted in reduced bFGF binding to low-affinity receptors and reduced mitogenic response to bFGF, suggesting that the TGF-beta-stimulated increase of low-affinity receptors in these cells contributes to the observed enhanced mitogenic effects of bFGF. Abnormal responses of scleroderma fibroblasts to TGF-beta/bFGF stimulation, particularly failure to synthesize low-affinity receptors in response to TGF-beta, adds a new characteristic to the fibrotic phenotype of scleroderma fibroblasts.

Adult↗
PubMed1992

Anemia of inflammation: role of T lymphocyte activating factor.

Varied conditions associated with immune activation (rheumatic, infectious and malignant) are associated with a syndrome characterized by selective erythropoietic suppression. The pathogenesis of this anemia is unknown. We have cultured intact marrows from 11 patients and found decreased erythroid colony forming activity (CFU-E: colony forming unit-erythroid; p < 0.01). We analyzed sera from 23 patients with infectious, rheumatic and malignant disorders for their ability to render normal human T lymphocytes inhibitory to autologous CFU-E and burst forming unit-erythroid in vitro. Following exposure to serum from some anemic patients, normal T cells were observed to inhibit autologous CFU-E when compared to the effect elicited by T cells incubated with heterologous normal serum. Pooled data from 19 (7 not anemic, 12 anemic) serum samples using 8 different normal T cell and marrow donors revealed a significant correlation (r = 0.65, p < 0.01) between each patient's hemoglobin level and the ability of his/her serum to render T cells suppressive to CFU-E in vitro. The suppression mediated by patient serum exposed T cells on autologous CFU-E could be ameliorated by increased concentrations of erythropoietin. The serum factor was heat stable (56 degrees C) and could not be eliminated by neutralizing antibody to either gamma-interferon or tumor necrosis factor-alpha. We conclude that some patients with anemia of inflammation may have a circulating factor(s) which renders normal T lymphocytes suppressive to autologous CFU-E in vitro. The presence of a circulating serum factor in these patients may help explain how inflammatory events distant from the marrow mediate the erythropoietic suppression characteristic of this syndrome.

Adolescent↗
PubMed1992

The biological activity of glyphosate to plants and animals: a literature review.

Glyphosate is a widely-used broad-spectrum herbicide with little to no hazard to man or the environment. Glyphosate is highly effective against 90 kinds of emerged grasses, brush and broad-leaf weeds. There is no residual soil activity, it does not leach into non-target areas, and it is non-volatile. It is practically nontoxic to mammals, birds and fish, showing no bioaccumulation in the food chain; it is biodegraded into natural products. When used correctly, glyphosate poses no threat to the environment and its inhabitants.

Animals↗
PubMed1992

Connective tissue metabolism including cytokines in scleroderma.

Scleroderma fibrotic lesions demonstrate vascular disease, mononuclear cell infiltrates, and increased collagen. Fibroblasts in these lesions are activated to synthesize increased extracellular matrix substances, a phenotype that continues when these cells are removed and grown in tissue culture. Levels of messenger RNA for connective-tissue substances, measured directly in biopsies of scleroderma skin, show increased message for type I collagen, but not type III collagen or fibronectin. Increased procollagen type I in scleroderma skin occurs in the papillary dermis, perivascular areas, and deep interstitium, even in skin areas that are not yet fibrotic. Scleroderma fibroblasts express more intercellular adhesion molecule 1 on their surfaces than do normal cells, and this molecule is increased in endothelial cells, mononuclear cells, and fibroblasts. In vitro scleroderma fibroblasts adhere more frequently to extracellular matrix substances and retract collagen lattices to a greater extent. Peripheral blood lymphocytes from scleroderma patients produce excessive amounts of interleukin-2 when incubated with type I collagen, and circulating basophils release more histamine than do normal cells. There is evidence for activated eosinophils both in the dermis and pulmonary lesions in scleroderma, which may play a role in fibrosis. Transforming growth factor-beta is overexpressed by alveolar macrophages from patients with fibrotic pulmonary disease. Scleroderma fibroblasts, when exposed to transforming growth factor-beta, overexpress the alpha-type receptor for platelet-derived growth factor. Scleroderma sera more frequently contain measurable quantities of interleukin-4, interleukin-6, and interleukin-2. Interleukin-4 causes adult dermal fibroblasts to proliferate and to make interleukin-6. Interleukin-6 has been shown to stimulate fibroblast synthesis of collagen and glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Adhesion Molecules↗
PubMed1992

Growth and characterization of fibroblasts obtained from bronchoalveolar lavage of patients with scleroderma.

We describe the detection and the growth of fibroblasts with human smooth muscle cell differentiation features from bronchoalveolar lavage (BAL) fluid of 53% of patients with scleroderma, but not from healthy controls. The binding of alpha-actin, vimentin and desmin antibodies by scleroderma lung fibroblasts exceeded that of normal adult lung fibroblasts, indicating that scleroderma lung fibroblasts express some markers of human smooth muscle cell differentiation (myofibroblasts), which may account for differences in biological behavior. A mesenchymal cell phenotype was documented by mRNA analysis, showing high expression of collagen type I and fibronectin in these cells. Fibronectin is also released in significantly higher amounts by scleroderma alveolar macrophages than by macrophages from healthy donors.

Actins↗
PubMed1991

Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5.

The mouse W19H mutation is an x-ray-induced deletion of more than 2 centimorgans on chromosome 5 encompassing the white spotting mutation W (encoded by the Kit protooncogene), patch (Ph), and recessive lethal (l) loci. The platelet-derived growth factor receptor alpha gene (PDGFRA) like Kit encodes a transmembrane receptor tyrosine kinase. By using mouse-Chinese hamster somatic cell hybrids and haplotype analysis in interspecific backcross mice, mouse Pdgfra was mapped to chromosome 5 in tight linkage with Kit. Hybridization of a PDGFRA probe to DNAs from W19H/ + heterozygous mice and patch heterozygous mice, and their wild-type littermates, demonstrated deletion of Pdgfra. Pulsed-field gel electrophoresis indicated that Kit and Pdgfra are linked on a 630-kilobase Mlu I DNA fragment. Thus the W19H deletion removes at least two receptor tyrosine kinases and the results suggest Pdgfra as a candidate for the Ph locus.

Animals↗
PubMed1978

Measurement of the bioavailability of iron, using the rat hemoglobin repletion test.

Variations in the AOAC official first action rat hemoglobin repletion test for iron were studied. These changes included (1) use of a simplified basal diet to eliminate ingredients which sometimes contribute too much iron; (2) increased fortification of the basal diet with vitamin E, pantothenic acid, and pyridoxine; (3) increased dietary copper; (4) variations in the carbohydrate source in the basal diet; (5) changes in the length of the depletion and repletion periods; and (6) comparison of prophylactic and curative procedures. The changes yielded results comparable to those obtained with the present official method. Further study may reveal that the depletion period can be shortened or eliminated. To fully meet the rat's vitamin requirements, increased levels of vitamin E, pantothenic acid, and pyridoxine are recommended. It is further recommended that the present method remain in official first action status, and that study be continued.

Animals↗