From the National Institutes of Health.
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Alcoholism↗
Biomedical subjects
D Alexander
Publications and source records attributed to D Alexander.
Does co-aggregation of the CD45 and CD3 antigens inhibit T cell antigen receptor complex-mediated activation of phospholipase C and protein kinase C?
The binding of agonistic monoclonal antibodies (mAb) to the CD3 antigen in T cells induces a rapid increase in tyrosine phosphorylation, inositive phosphate (IP) production, a rise in intracellular calcium and protein kinase C (PKC) activation. These intracellular signals have been implicated in the control of interleukin-2 and interleukin-2R receptor gene expression, thereby regulating T cell proliferation. Previous studies have shown that co-ligation of the CD45 and CD3 antigens inhibits CD3-induced tyrosine phosphorylation, IP production, calcium signals and T cell proliferation. It has therefore been suggested that the CD45 antigen uncouples the T cell receptor (TcR) from mitogenic signal pathways. In this study co-ligation of the CD3 and CD45 antigens with precisely constructed bispecific mAb did not inhibit CD3-induced T cell proliferation, IP production, calcium signals, diacylglycerol production or PKC activation. Furthermore, co-ligation of CD3 and CD45 antigens already cross-linked with IgM mAb did not lead to inhibition of CD3-induced calcium signals. Inhibitions of CD3-induced intracellular signals were observed following co-ligation of IgG CD45 and CD3 mAb with anti-IgG (F(ab')2 fragments. However, comparable inhibitions were also noted following co-ligation of CD3 with other abundant cell-surface antigens such as CD5 and LFA-1, and inhibitions were only observed when the CD3 mAb used required cross-linking to induce signals. These results suggested that the inhibitory effects of CD45 IgG mAb were not specific and were caused by the prevention of CD3-CD3 cross-linking following CD3 antigen co-ligation with other cell surface molecules. These findings are inconsistent with a specific inhibitory role for the CD45 phosphotyrosine phosphatase in uncoupling the TcR from mitogenic signal pathways.
Antibodies, Monoclonal↗
CD45 tyrosine phosphatase-activated p59fyn couples the T cell antigen receptor to pathways of diacylglycerol production, protein kinase C activation and calcium influx.
The role of the CD45 phosphotyrosine phosphatase in coupling the T cell antigen receptor complex (TCR) to intracellular signals was investigated. CD45- HPB-ALL T cells were transfected with cDNA encoding the CD45RA+B+C- isoform. The tyrosine kinase activity of p59fyn was found to be 65% less in CD45- cells than in CD45+ cells, whereas p56lck kinase activity was comparable in both sub-clones. In CD45- cells the TCR was uncoupled from protein tyrosine phosphorylation, phospholipase C gamma 1 regulation, inositol phosphate production, calcium signals, diacylglycerol production and protein kinase C activation. Restoration of TCR coupling to all these pathways correlated with the increased p59fyn activity observed in CD45-transfected cells. Co-aggregation of CD4- or CD8-p56lck kinase with the TCR in CD45- cells restored TCR-induced protein tyrosine phosphorylation, phospholipase C gamma 1 regulation and calcium signals. Receptor-mediated calcium signals were largely due (60-90%) to Ca2+ influx, and only a minor component (10-40%) was caused by Ca2+ release from intracellular stores. Maximal CD3-mediated Ca2+ influx occurred at CD3 mAb concentrations at which inositol phosphate production was non-detectable. These results indicate that CD45-regulated p59fyn plays a critical role in coupling the TCR to specific intracellular signalling pathways and that CD4- or CD8-p56lck can only restore signal transduction coupling in CD45- cells when brought into close association with the TCR.
Biological Transport↗
Erythropoietic adaptations to endurance training.
Erythropoietic adaptations involving the oxygen dissociation curve (ODC) and erythropoietin production have been implicated in the etiology of reduced blood haemoglobin concentrations in sportspersons (known as sports anaemia). A significant increase in the half-saturation pressure indicating a right-shift in the ODC was measured in 34 male [25.8-27.4 mmHg (3.44-3.65 kPa)] and 16 female (25.8-27.7 mmHg (3.44-3.69 kPa)] trained distance runners (P less than 0.01 for both genders) after completing a standard 42-km marathon. Erythrocyte 2,3-diphosphoglycerate concentrations measured concurrently were unaltered by exercise, although consistently higher in the female compared to the male athletes (P less than 0.05). The serum erythropoietin (EPO) concentrations of 15 male triathletes (26.3 U.ml-1) were significantly lower than those of 45 male distance runners (31.6 U.ml-1; P less than 0.05). However, the mean serum EPO concentrations of male and female athletes engaged in a variety of sports were not different from those of sedentary control subjects of both sexes (26.5-35.3 U.ml-1). Furthermore, the serum EPO concentrations were unaltered after prolonged strenuous exercise in 20 male marathon runners. These data suggest that the haematological status of these endurance athletes is in fact normal and that the observed shift in the ODC, while providing a physiological advantage during exercise, has no measurable effect on the erythropoietic drive.
2,3-Diphosphoglycerate↗
Characterization of the hepatitis C virus E2/NS1 gene product expressed in mammalian cells.
Truncated and full-length versions of the hepatitis C virus protein domain encoding a presumptive envelope glycoprotein designated E2/NS1 were stably expressed in CHO cell lines. Characterization of the processing events involved in the maturation of E2/NS1 revealed that a high-mannose form resident in the endoplasmic reticulum was the most abundant form detected intracellularly. The ionophore carboxyl cyanide m-chlorophenyl-hydrazone was used to show that the E2/NS1 glycoprotein resided in the endoplasmic reticulum. The full-length form of E2/NS1 appeared to be cell-associated and could not be detected as a secreted product. C-terminal truncated molecules could be detected in the extracellular media as fully processed glycoproteins containing terminal sialic acid additions. These truncated glycoproteins are predicted to be biologically relevant targets of the host immune response and are therefore potential subunit vaccine candidates.
Animals↗
The role of CD45 in T-cell activation--resolving the paradoxes?
CD45 is one of the most abundant transmembrane glycoproteins expressed on the surface of haematopoietic cells. Despite the striking advances of the past few years in the understanding of the actions of CD45 at a molecular level, several paradoxes remain. This article argues that these paradoxes are more apparent than real, and suggests that CD45 plays a key role on the T-cell surface in regulating coupling of the antigen-receptor complex to intracellular signalling pathways.
CD3 Complex↗
Evidence for the indirect utilization of glucose for the synthesis of hepatic glycogen in man.
1. This study was designed to test the hypothesis that three-carbon intermediates can be used in the 'indirect' pathway of glycogen synthesis in human liver (i.e. a route additional to the use of glucose by the 'direct' pathway). 2. After an overnight fast, 13 patients were given an infusion of 20% (w/v) glucose before elective abdominal operation. All received a 2.5 g bolus of 2220 kBq of selectively 3H- and 14C-labelled glucose before removal of a 1 g biopsy of liver. 3H and 14C were determined in purified glycogen as well as in glucose and lactate from samples of peripheral blood. 3. The ratio and specific activities of 3H and 14C in glycogen were found to be significantly lower than those in administered glucose. By calculation, 7-74% of glycogen repletion occurred by indirect pathways and not all of this was from the glucose supplied. 4. This study suggests that the operation of a direct pathway in man is not exclusive and that significant repletion of hepatic glycogen occurs by an indirect route.
Adult↗
One hundred requests for predictive testing for Huntington's disease.
In Grampian region, the first 100 requests for predictive testing for Huntington's disease have been analysed. Forty-five presymptomatic predictive test results have been given, eleven families have made a decision to undergo prenatal exclusion tests, and so far eleven pregnancies have been investigated using chorion villus biopsy. This paper presents the protocol used and a descriptive analysis of those receiving results, those choosing to leave the programme, and those unable to complete it because of an unsuitable family structure or unco-operative relatives.
Adult↗
Analysis of strike-through contamination in saturated sterile dressings.
The method of saturating gauze sponges directly in their wrapper was tested to determine strike-through contamination. Contamination occurred in 100% of the uncoated-wrapper sponges, regardless of exposure to Staphylococcus epidermidis or Escherichia coli. Among coated-wrapper sponges, 80% exposed to Staphylococcus epidermidis and 20% exposed to Escherichia coli demonstrated strike-through contamination. Coated-wrapper sponges had a significantly lower rate of contamination than uncoated-wrapper sponges when exposed to Escherichia coli. Occurrence of contamination of all sponges was significantly higher from Staphylococcus epidermidis. The findings render the popular practice of saturating gauze sponges in their wrapper unacceptable.
Bandages↗
Differential tissue regulation of insulin-like growth factor binding proteins in experimental diabetes mellitus in the rat.
The expression and regulation of IGF-I is tissue-specific in diabetes mellitus in the rat. These studies were designed to examine if similar tissue specificity exists for IGF-BPs in the diabetic milieu. Diabetes mellitus was induced by a single i.p. injection of STZ (100 mg/kg body weight). Rats were treated with either vehicle--insulin, vanadate, or phlorizin for 7-14 days. Tissues were analyzed for IGF-BPs by ligand blotting and by affinity cross-linking and immunoprecipitation. In liver tissue from nondiabetic control rats, multiple forms of IGF-BPs were noted, ranging from 48,000 to 25,000 M(r). In diabetic rat liver tissue, the 25,000-M(r) form was unchanged, whereas the higher M(r) forms (48,000-42,000 M(r)) were decreased, and the 30,000-M(r) form was increased. Insulin therapy of diabetic rats decreased all forms to below control levels. In the kidney tissue of control rats, faint IGF-BP bands were seen at 30,000 and 25,000 M(r). In diabetic rat kidney tissue, the 30,000-M(r) form again was increased (as in liver) and restored to control levels with insulin therapy. In contrast, only a 30,000-M(r) band was seen in control pituitary tissue, which was slightly increased in the diabetic rats and also was decreased below control levels by insulin. In hypothalamus and cerebral cortex tissue, bands at 30,000 and 25,000 M(r) were noted, and neither was altered by diabetes or insulin treatment. Treatment of diabetic rats with vanadate and phlorizin resulted in comparable blood glucose levels, which were only slightly higher than those achieved with insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Is fatal pancreatitis a consequence of excessive leukocyte stimulation? The role of tumor necrosis factor alpha.
This study examines the possible role of excessive leukocyte stimulation in the pathogenesis of acute pancreatitis. Levels of tumor necrosis factor alpha (TNF-alpha) and elastase-alpha 1 proteinase inhibitor (E-alpha 1PI) have been measured as markers of macrophage and neutrophil activation, respectively, in serial plasma samples from 27 patients with acute pancreatitis. Levels of TNF-alpha did not support the possibility of excessive macrophage activation, but raised levels of E-alpha 1PI in patients with either the mild or severe form of the illness indicated the activation of neutrophils. Whether this is a consequence of the illness or is a contributory factor in the pathogenesis is not clear.
Acute Disease↗
Strenuous exercise: analogous to the acute-phase response?
1. It has been suggested that the physiological consequences of strenuous exercise are analogous to those of the acute-phase response. 2. In 70 male and 20 female competitive distance runners, a marked, but transient, neutrophil leucocytosis occurred immediately after these athletes completed a standard (42 km) marathon race. Concomitant significant increases were noted in the plasma cortisol levels, creatine kinase activity, C-reactive protein level, total protein level and albumin level (P less than 0.01). 3. The plasma fibrinogen, C-reactive protein and total protein concentrations were markedly increased both 24 h and 48 h after exercise (P less than 0.01). The serum haptoglobin level was significantly decreased after exercise (P less than 0.01), and increased 48 h later (P less than 0.05). There was no change in the serum iron level, total iron-binding capacity, per cent saturation of transferrin and serum ferritin level. 4. A significant increase in interleukin-1-type activity was demonstrated immediately and 24 h after exercise (P less than 0.01). 5. It is concluded that the metabolic sequelae of sustained exercise are similar, but not analogous, to the acute-phase response, and interleukin-1, probably plays a significant role in linking the haematological and immunological changes observed after sustained strenuous exercise.
Acute-Phase Proteins↗
AIDS education for labor and management: category III workers.
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Acquired Immunodeficiency Syndrome↗
The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy.
The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.
Animals↗
Alpha 2 macroglobulin state in acute pancreatitis. Raised values of alpha 2 macroglobulin-protease complexes in severe and mild attacks.
Plasma values of C reactive protein, alpha 1 proteinase inhibitor, alpha 2 macroglobulin, and complexed alpha 2 macroglobulin have been determined in serial samples from 27 patients with acute pancreatitis. Complexed alpha 2 macroglobulin was measured by a novel enzyme linked immunosorbent assay with a monoclonal antibody specific for the complexed form. Patients with severe illness had lower concentrations of total alpha 2 macroglobulin and higher concentrations of complexed alpha 2 macroglobulin than those with mild illness, and in the majority of severe attacks the abnormal amounts of complexed alpha 2 macroglobulin were present throughout the eight days of the study. The proportion of total alpha 2 macroglobulin in the uncomplexed form, however, was generally greater than 90%, and in 26% of the mild cases completely normal concentrations of uncomplexed alpha 2 macroglobulin (greater than 99% of total) were found throughout the eight days of the study. This suggests that exhaustion of alpha 2 macroglobulin in plasma is unlikely to be a major factor in the pathogenesis of acute pancreatitis.
Acute Disease↗
Effect of otitis media on infrared tympanic thermometry.
This study was designed to determine if temperature readings using a new tympanic thermometer are affected by otitis media. These readings were also compared to a rectal or oral temperature. Eighty-four children with unilateral suppurative or non-suppurative otitis media diagnosed clinically by their pediatricians were enrolled in the study. Temperatures were measured in both ears using the Thermoscan PRO-1 Instant Thermometer and rectally or orally by a glass or electronic predictive thermometer. For 67 children with unilateral suppurative otitis media the mean temperature in infected ears was 0.38 degrees Fahrenheit higher than in uninfected ears (p = .005). Neither temperatures measured in affected nor those from unaffected ears differed significantly from oral or rectal control readings. For 17 children with unilateral non-suppurative otitis media there was no statistically significant difference between temperatures in affected and unaffected ears or between the temperatures in either ear and the oral or rectal control. Our data show that temperatures taken in ears with suppurative otitis media are slightly higher than those in normal ears. This difference is of minimal clinical significance and does not affect the accuracy when compared to oral or rectal control readings.
Body Temperature↗
Responses of children, parents, and nurses to tympanic thermometry in the pediatric office.
This study was designed to assess children's behavioral responses to tympanic thermometry. In addition, parents' and nurses' impressions of this new technology were evaluated. 224 patients were enrolled from three private pediatric practices. Patients were alternately assigned to have their temperature taken with either a tympanic thermometer or with a rectal or oral thermometer. Parents and nurses were then asked to fill out a short questionnaire to describe their observations of the child's behavior during temperature taking and to describe their own feelings about the temperature taking method used. Parents were also asked to assess their usual method of temperature taking at home and their child's usual behavioral response. Tympanic thermometry was rated higher by both parents and nurses for speed, ease, cleanliness, and safety. Parents and nurses were more confident in the accuracy of traditional temperature taking methods. Children whose temperatures were taken rectally were more likely to be observed by both parents (p = .02) and nurses (p = .01) to have a negative behavioral reaction to the procedure than children whose temperatures were taken by tympanic thermometry. There was no difference observed between the behavioral responses of children who had temperatures taken orally and those who had tympanic thermometry.
Adolescent↗