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Biomedical subjects

B Richardson

Publications and source records attributed to B Richardson.

At least 91 records · Page 5Linked to original sources
PubMed1989

The effects of hypoxemia with progressive acidemia on fetal renal function in sheep.

In order to determine the effects of fetal hypoxemia on renal blood flow, glomerular filtration rate (GFR) and urethral and urachal urine output, we examined the effects of 3 h maternally-induced (9% O2, 3% CO2, 88% N2) fetal hypoxaemia on 10 chronically-instrumented fetal sheep between 127-135 days of gestation. Fetal arterial pH fell significantly during the second and third hours of hypoxia and this coincided with a significant increase in fetal arterial blood pressure (P less than 0.05). During the second hour of hypoxia, with mild acidaemia, fetal GFR decreased significantly and then, during the third hour, fetal GFR, urethral and total urine output were significantly elevated. During the 2-h recovery period urachal and total, but not urethral urine output, were significantly elevated (P less than 0.05). The data suggested that the increase in GFR and urine output measured during the third hour of hypoxia and the recovery period may reflect a pressure diuresis.

Animals↗
PubMed1989

Activity of alcohol dehydrogenase and aldehyde dehydrogenase in maternal liver, fetal liver and placenta of the near-term pregnant ewe.

The activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) was determined in the near-term pregnant ewe. There was little ADH activity in fetal liver (4.4%) and placenta (0.2%) compared with maternal liver. Low KM (microM acetaldehyde) ALDH activity was similar in the three tissues. High KM (mM acetaldehyde) ALDH activity was less in fetal liver (57%) and placenta (16%) compared with maternal liver. These data and the pharmacokinetics of ethanol and its proximate metabolite, acetaldehyde, in the near-term pregnant ewe indicate that ethanol elimination from the maternal-fetal unit is regulated primarily by maternal hepatic ADH-catalyzed biotransformation of ethanol, and low KM ALDH activity in the fetal liver and placenta protects the fetus from exposure to ethanol-derived acetaldehyde, which is produced primarily in the maternal compartment.

Acetaldehyde↗
PubMed1989

Identification of a cellular polypeptide that distinguishes between acute lymphoblastic leukemia in infants and in older children.

We analyzed the polypeptide pattern of leukemic cells of infants and older children with acute lymphoblastic leukemia (ALL), using two-dimensional polyacrylamide gel electrophoresis (PAGE). Patterns were analyzed for the occurrence of a previously detected cytosolic polypeptide, designated L3. Quantitative analysis of L3 in 12 infants and 91 older children with non-T ALL indicated lack of expression of polypeptide L3 in leukemic cells of infants which, in most cases, expressed HLA-DR and CD19 and lacked CD10. Quantitative analysis of L3 in relation to cell surface marker expression revealed that L3 was limited in its occurrence to non-T ALL and was not coordinately expressed with any of the surface markers included in the study. Among patients in the HLA-DR-positive, CD19-positive, and CD10-negative group, different levels of polypeptide L3 were observed between infants and older children. These results indicate differences in leukemic cell constituents between infants and older children with ALL and an otherwise similar cell surface marker phenotype.

Adolescent↗
PubMed1988

Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.

Inhibitors of DNA methylation, such as 5-azacytidine, induce gene expression. We have previously reported that cloned T cells treated with 5-azacytidine lose the requirement for Ag and can be activated by autologous HLA-D molecules alone, thus becoming auto-reactive. This phenomenon could potentially mediate an autoimmune disease in vivo. Inasmuch as several drugs are known to cause autoimmune disease, we asked whether they exert the same effects on T cells as 5-azacytidine. We report that hydralazine and procainamide, two drugs associated with a lupus-like autoimmune disease, also inhibit DNA methylation and induce self-reactivity in cloned T cell lines. These results suggest that drug-induced autoimmune disease may be due to activation of as yet unidentified genes through mechanisms involving DNA methylation.

Autoimmune Diseases↗
PubMed1988

N-acetylprocainamide is a less potent inducer of T cell autoreactivity than procainamide.

We have reported that an inhibitor of DNA methylation, 5-azacytidine, makes cloned, antigen-specific CD4+ T cells autoreactive, and that procainamide and hydralazine mimic this effect. Those results suggested that procainamide and hydralazine may induce autoimmunity by inhibiting DNA methylation and causing T cell autoreactivity. We report now that N-acetylprocainamide, a procainamide derivative that does not induce lupus, is also a DNA methylation inhibitor, but it is 100 times less potent than procainamide in inducing T cell autoreactivity.

Acecainide↗
PubMed1988

The role of carbon dioxide in the generation of human fetal breathing movements.

To determine the role of carbon dioxide in the generation of fetal respiratory movements, the effect of induced maternal hypocapnia and hypercapnia on fetal breathing movements, gross body movements, and fetal heart rate was studied in 12 healthy pregnant women near term. Patients were studied for a 1-hour control period breathing room air followed by four randomized 15-minute study periods with patients breathing either room air, a prepared gas mixture with 2% or 4% carbon dioxide, or undergoing controlled hyperventilation as determined by monitoring end-tidal PCO2. The percentage of time fetal breathing movements correlated significantly with maternal end-tidal PCO2 (r = 0.62, p less than 0.01), increasing with maternal breathing of 2% and 4% carbon dioxide and decreasing with maternal hyperventilation. Fetal gross body movements, fetal heart rate, and fetal heart rate variability showed no significant changes. It is concluded that as in adults, the carbon dioxide level in fetuses is an important stimulus for the generation of respiratory movements, acting independent of a change in behavioral state. It is hypothesized that tonic carbon dioxide level input is an important determinant of fetal respiratory center drive, but little or no phasic carbon dioxide input exists because of continuous placental excretion, thus resulting in the episodic occurrence of breathing movements with changes in the fetal behavioral state.

Adult↗
PubMed1988

Effects of multiple-dose maternal ethanol infusion on fetal cardiovascular and brain activity in lambs.

Ethanol (2 gm/kg of maternal body weight administered in four equal doses of 0.5 gm/kg over 5 hours) was infused intravenously into nine chronically prepared pregnant ewes between 124 and 137 days' gestation. The data demonstrated a dose-response relationship between fetal arterial ethanol concentrations and the incidence of fetal breathing movements. Suppression of normal fetal electrocortical activity occurred at a low ethanol concentration and returned to control values at a time of very high arterial ethanol concentrations. This experimental model of a binge drinking episode further supports the hypothesis that ethanol suppresses fetal breathing movements by a direct central mechanism rather than indirectly by alteration of electrocortical activity.

Animals↗
PubMed1988

Sandimmun (cyclosporin A): mode of action and clinical results in rheumatoid arthritis.

Cyclosporin A (Sandimmun) has gained wide acceptance by most transplant physicians as the immunosuppressant of choice for preventing rejection of solid organ grafts and graft-versus-host disease. The drug has a specific effect on T-lymphocytes in which it seems to prevent the transcription of genes for several lymphokines. The reduction in IL-2 prevents the clonal expansion of T-lymphocytes and their differentiation into effector T-cells. The reduction in IFN-tau interrupts the feedback mechanism between T-cells and macrophages and the aberrant expression of MHC class II molecules. Through these mechanisms Sandimmun exerts an immunosuppressive and anti-inflammatory effect. Considerable evidence has accumulated to suggest that rheumatoid arthritis (RA) is an auto-immune disease. Activated T-lymphocytes interrelate with macrophages, other inflammatory cells and effector cells in joint tissue, leading to symptoms of inflammation accompanied by joint destruction. Immunosuppressive treatment is already well established in this disease and several trials have already taken place using Sandimmun. A total of 224 patients with RA refractory to conventional disease-modifying drugs have participated in 11 published clinical studies. A review of these studies concludes that Sandimmun is efficacious in controlling inflammatory and functional symptoms, although this improvement is no generally accompanied by reductions in ESR and rheumatoid factor. The frequency of adverse events is comparable to that of other treatments but nephropathy remains the principal factor limiting the use of Sandimmun. Recent evidence suggests that with a strict dosage strategy and good monitoring this problem is controllable and reversible. Further studies are under way to confirm these claims.

Animals↗
PubMed1988

B cell activation in patients with active procainamide induced lupus.

Cellular immune abnormalities have been described in asymptomatic patients receiving procainamide therapy, but not in patients with active procainamide induced lupus. We tested patients with active procainamide lupus for evidence of T or B cell activation similar to that observed in idiopathic lupus. Symptomatic patients had a significant increase in spontaneous IgG synthesis, but T cells bearing activation markers were not significantly different from age matched controls. Our results demonstrate that patients with active procainamide lupus have evidence for B cell activation, similar to idiopathic lupus.

Aged↗
PubMed1987

Cerebral oxidative metabolism in fetal sheep with multiple-dose ethanol infusion.

Cerebral oxidative metabolism and cotylendonary blood flow were measured in 10 unanesthetized fetal sheep (127 to 132 days' gestation) during a control period, after the first, third, and fourth infusions of four doses of 0.5 gm of ethanol per kilogram of maternal body weight infused into the ewe during 5 hours, and 24 hours after ethanol infusion. Preductal arterial and sagittal vein blood samples were analyzed for oxygen content, blood gases, pH, and ethanol. Cerebral and cotylendonary blood flow were measured with a radioactive microsphere technique. Fetal blood gases and pH changed little with the ethanol infusions, although PaO2 and oxygen content decreased 24 hours after ethanol infusion. Cotylendonary blood flow, which was decreased after the third and fourth ethanol infusions, did not account for these delayed hypoxemic changes. Similarly, cerebral oxidative metabolism was decreased when measured after each of the ethanol infusions, with no dose response or tolerance evident. This noted fall in fetal cerebral oxidative metabolism appears to be a direct depressant effect that was maximal at rather low fetal ethanol levels, which, if prolonged, might well affect cerebral growth and development. Recovery of cerebral metabolic function appeared complete by 24 hours. However, relative fetal hypoxemia was evident at this time, the mechanism of which remains to be determined.

Animals↗
PubMed1987

Disposition of acute, multiple-dose ethanol in the near-term pregnant ewe.

The disposition of ethanol and its proximate metabolite, acetaldehyde, was determined in seven conscious instrumented pregnant ewes (127 to 132 days of gestation; term, 147 days) for intravenous infusion of four dosages of 0.5 gm ethanol/kg maternal body weight, administered over 5 hours to the mother. The maternal and fetal blood had ethanol concentrations that were maximal at 5 hours and were virtually identical during the 24-hour study. There was delayed transfer of ethanol into the amniotic and allantoic fluids during the dosing period, followed by higher ethanol concentrations in these fluids during the elimination phase compared with fetal blood. The ethanol elimination rate was similar for the four biologic fluids. Acetaldehyde concentrations in the four fluids were a thousandfold less than the respective ethanol concentrations. The maternal blood acetaldehyde concentration was greater than that in fetal blood. The data indicate that for a binge-type drinking episode during near-term pregnancy, there is unimpeded bidirectional placental transfer of ethanol between the mother and the fetus; the amniotic fluid surrounding the fetus is a reservoir for ethanol in utero; elimination of ethanol from the maternal-fetal unit is regulated by maternal hepatic biotransformation of ethanol; and there is appreciable acetaldehyde-oxidizing capacity in the maternal liver and at extrahepatic sites.

Acetaldehyde↗
PubMed1987

The role of fetal urinary excretion in the transfer of ethanol into amniotic fluid after maternal administration of ethanol to the near-term pregnant ewe.

The objective of this study was to determine whether fetal urinary excretion is a major route of ethanol transfer into the amniotic fluid surrounding the fetus following maternal administration of ethanol. Conscious instrumented pregnant ewes between 130 and 137 days' gestation (term, 147 days) with (n = 3) or without (n = 3) a catheter in the fetal bladder were administered 1 g ethanol/kg maternal body weight as a 1-h maternal intravenous infusion. Maternal blood, fetal blood, and amniotic fluid samples were collected at selected times, and fetal urine was collected continuously from the bladder-cannulated fetus during the 14-h study for the determination of ethanol concentrations. Fetal urinary excretion of ethanol occurred, and the total amount of ethanol excreted represented 0.30 +/- 0.07 (SD)% of the maternal ethanol dose. The renal clearance of ethanol by the fetus was 0.43 +/- 0.06 mL/min. The pharmacokinetics of ethanol in the maternal-fetal unit and the amniotic fluid for the bladder-cannulated fetal preparation were similar to the data for the nonbladder-cannulated preparation. The data indicate that fetal urinary excretion of ethanol is a secondary route of ethanol transfer into the amniotic fluid. It would appear that diffusion of ethanol across membranes from the maternal and fetal circulations is a major route of ethanol transfer into this intrauterine compartment.

Amniotic Fluid↗
PubMed1987

Assault experiences of 100 psychiatric inpatients: evidence of the need for routine inquiry.

The authors obtained complete histories of all experiences of being physically or sexually assaulted from 100 psychiatric inpatients, using a structured interview with well-defined assault scales and a detailed inquiry into circumstances surrounding the assault. The majority (81%) of patients had experienced major physical and/or sexual assault. The circumstances associated with the assaults, the patients' perceptions of the effects of the assaults, and previous therapists' lack of awareness of the assaults are discussed. On the basis of these findings the authors recommend routine inquiry into patients' assault history.

Adolescent↗
PubMed1986

Effect of an inhibitor of DNA methylation on T cells. I. 5-Azacytidine induces T4 expression on T8+ T cells.

Maturing thymocytes express a series of cell surface glycoproteins which can be identified by monoclonal antibodies. The stage II or common thymocyte expresses the phenotype T4+T8+T6+T3-. In response to unknown signals, but presumably involving interactions with products of the major histocompatibility complex, the thymocyte suppresses either the T8 or T4 gene, becoming committed to the T4+T8- or T4-T8+ phenotype. With maturation, the thymocyte also becomes T6-T3+. To study whether DNA methylation may be involved in regulating expression of these determinants in mature T cells, we treated cloned interleukin 2-dependent T8- and T4-bearing T cells with 5-azacytidine (5-azaC), a nucleoside analog which inhibits methylation of newly synthesized DNA. In this report, we show that T8+ T cells treated with 5-azaC express the phenotype T8+T4+T6-T3+. Treatment of the same cells with hydroxyurea, an inhibitor of DNA synthesis, failed to induce T4 on T8+ cells. These results suggest that expression of the T4 gene may be suppressed by DNA methylation in mature T8+ cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells.

During T-cell maturation, thymocytes interact with thymic stromal major histocompatibility complex (MHC) determinants and thymic hormones, and proliferate, apparently in response to MHC gene products, in the absence of antigen. The maturing thymocytes also express a series of cell surface molecules, at one stage coexpressing T4, T6, and T8. Mature T cells express either T4 or T8, lack T6, bear the T3-Ti receptor complex on the cell surface, and require antigen in addition to MHC determinants to proliferate. To study whether DNA methylation may be involved in regulating phenotypic and functional changes observed during thymocyte maturation, cloned, T4+ Interleukin-2 dependent, antigen-specific T cells were treated with an inhibitor of DNA methylation, 5-azacytidine (5-azaC). The 5-azaC treated cells lost the requirement for antigen and could be activated by autologous macrophages alone. Anti-class II and anti-T3, but not anti-class I monoclonal antibodies, inhibited activation of 5-azaC treated T4+ cells by macrophages, implying that the T3-Ti receptor complex may be recognizing class II MHC molecules without antigen. No changes in T3 and T4 expression were noted, and neither T8 nor T6 was induced.

Antibodies, Monoclonal↗
PubMed1986

Effects of prostaglandins on the pulmonary vascular bed of newborn rats with chronic hypoxia.

We investigated the effects of prostaglandins (PG) E1, I2 and D2 on the pulmonary vascular bed of newborn rats subjected to chronic hypoxia. Forty seven newborn rats were exposed to chronic hypoxia (10% oxygen) for 23 days and divided into five groups which received PGE1 (N = 10), PGI2 (N = 9), PGD2 (N = 11), placebo (N = 9) or served as controls (N = 8). The PG's were administered by implanting slow release subcutaneous pellets delivering an average daily dose of 1 microgram. Thirteen newborn rats in room air received either placebo or served as controls. All rats were killed after 23 days and heart-lung preparations were perfusion fixed with glutaraldehyde. Appropriate blocks were processed for quantitative morphometry of the pulmonary parenchyma, arteries and arterioles. For analysis the pulmonary vessels were grouped by external diameter, i.e. 30-50 mu and 50-100 mu. External diameter/lumen diameter, an index of medial smooth muscle mass, was 1.39 +/- 0.02 in room air controls, this index of medial muscle mass was significantly increased (p less than 0.01) to 1.53 +/- 0.03 in hypoxic controls and the PGD2 and PGI2 groups. However, the PGE1 group did not have medial hypertrophy evidenced by a medial muscle mass index of 1.34 +/- 0.04, similar to room air controls. These findings suggest that PGE1 may prevent the development of medial hypertrophy that occurs in chronic hypoxia.

Alprostadil↗