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Biomedical subjects

J M Lipton

Publications and source records attributed to J M Lipton.

At least 145 records · Page 8Linked to original sources
PubMed1983

Beta-endorphin: effect on thermoregulation in aged monkeys.

In previous experiments small doses of the opiate morphine produced greater hyperthermia in aged than in younger sub-human primates. To test whether this augmented response is due to enhanced sensitivity of CNS opioid receptors with age, beta-endorphin (0.625-5 micrograms), an endogenous opioid peptide, was injected into the lateral cerebral ventricle (ICV) of young (less than 9 years) and aged (greater than 9 years) squirrel monkeys. Significantly greater hyperthermias developed in the older primates after each dose. In the aged monkeys, all but the smallest dose increased core temperature about 1.5 degrees C within 1 hr after injection. Mean rectal temperature in the younger animals rose 0.5-0.7 degrees after all but the largest dose (1-1.5 degrees C rise). Both groups maintained an elevated body temperature after central beta-endorphin throughout the 5 hr recording period. 1.25 micrograms beta-endorphin given ICV in a hot environment (30 degrees C) caused greater hyperthermia in older animals. This dose given in the cold (18 degrees C) caused large changes in temperature of the aged monkeys, either hyperthermia or marked decreases, whereas the young primates developed only moderate rises in body temperature. The same dose of morphine sulfate (1.25 micrograms) ICV produced similar changes in core temperature in the two age groups in each ambient temperature. These results indicate that: (1) stimulation of CNS opioid receptors influences thermoregulation and (2) aging increases responsiveness to such stimulation.

Age Factors↗
PubMed1983

Effects of morphine on body temperature of squirrel monkeys of various ages.

Increased sensitivity to certain drugs is believed to contribute to dysthermia in the elderly. To learn whether the temperature-altering effects of an opiate are increased in aged primates, injections of morphine sulfate (0.5-4 mg/kg) were given SC in randomly assigned order to squirrel monkeys ranging in age from 3.5 to over 17 years. Hyperthermia was the predominant response with no clear relationship to age, although hypothermic and biphasic responses also occurred, most commonly after the highest dose. Lateral cerebral ventricular injections of 0.625 and 1.25 micrograms morphine sulfate evoked hyperthermia in monkeys over 8 years of age but did not affect the temperature of animals less than 5 years old. Doses of 2.5 and 5 micrograms usually elicited hyperthermia regardless of age, but 10 micrograms induced hypothermia in a majority of monkeys. Naloxone was given intraventricularly to several monkeys to limit the degree of hypothermia after high doses of morphine given peripherally or centrally. Thus in these primates, as in other species such as the rat, lower doses of morphine usually evoked hyperthermia, but sufficiently high doses caused body temperature to fall. Unlike the case in the squirrel monkey with diazepam and with endogenous substances such as leukocytic pyrogen and taurine, there was not a strong or consistent relationship between age and morphine-induced temperature changes.

Aging↗
PubMed1983

Effects of alcohol on thermoregulation in aged monkeys.

Ethanol ingestion has been implicated in accidental hypothermia of the elderly, but there is no prior data on the relative sensitivity to alcohol of aged homeotherms that might account for disproportionate dysthermia in this age group. To assess their sensitivity, ethanol (0.5-2.0 g/kg) or H20 was given by gavage to squirrel monkeys less than 4 yrs old, 4-9 yrs of age and over 9 yrs old. Dose-related decreases in body temperature occurred in all three groups in a 25.5 degrees C environment, with the greatest decreases in the oldest animals. In an 18.5 degrees C environment the hypothermias caused by 0.5 and 1.0 g/kg ethanol were greatly augmented in old monkeys and in some cases their temperatures fell to potentially life-threatening levels. In a 30.5 degrees C environment, 1.0 g/kg ethanol given to monkeys caused approximately equal temperature reductions in the three groups. When determined after 1.0 g/kg ethanol, peripheral vasomotor tone increased significantly in animals of each age group in all three environments. Decreases in rectal temperature were associated with parallel decreases in oxygen consumption. These results indicate that: 1) aging is associated with an increased sensitivity to the hypothermic action of ethanol in thermoneutral and cold environments, 2) ethanol in the doses tested inhibits heat production mechanisms without suppressing compensatory vasoconstriction in response to decreased body temperature.

Aging↗
PubMed1983

The pathogenesis, diagnosis, and treatment of histiocytosis syndromes.

The histiocytosis syndromes previously known, and often still referred to, as histiocytosis-X were originally categorized by many as malignant neoplasms. They have been treated as such with aggressive chemotherapy and radiation therapy. Although these modalities are still used, there are significant differences between the histiocytosis syndromes and the true malignant disease that suggest conservative management for many patients. The clinical course of malignant neoplasia is relentlessly progressive with virtually no survival in untreated patients. The histiocytosis syndromes are characterized by frequent spontaneous remissions and exacerbations, with varying morbidity and survival in untreated patients, depending on the extent of the disease. Pathologically, the lesions of histiocytosis appear as reactive infiltrates, possessing little of the cellular atypicality and homogeneity characteristic of malignancy. Although the etiology of these phenomena is unknown, histiocytosis syndromes appear to represents a reactive autoimmune disorder triggered by unknown stimuli.

Antineoplastic Agents↗
PubMed1983

Evidence for genetic restriction in the suppression of erythropoiesis by a unique subset of T lymphocytes in man.

The suppression of erythropoiesis by lymphocytes from patients with a T cell lymphoproliferative syndrome and pure erythrocyte aplasia has been previously demonstrated. To study the nature of the suppressor cell and possible genetic restriction of this suppression, we investigated a patient with severe anemia, splenomegaly, lymphocytosis, and erythroid aplasia. A 3-mo course of low-dose daily oral cyclophosphamide achieved a complete remission for over 12 mo. The surface phenotype of his lymphocytes was analyzed by means of antibodies to lineage, differentiation, and activation-specific surface antigens. The cells expressed mature T cell antigens T3, T8, and T11, while lacking T1. Immature T cell, B cell, and the monocyte-specific antigen Mo2 were absent, while Mo1, a monocyte-associated antigen not normally expressed on T cells, was present. T10 and Ia expressed as activation antigens were also present. The cells, cryopreserved at diagnosis, were thawed and co-cultured in plasma clot with patient remission marrow samples at T cell/bone marrow ratios of 1:1 and 2:1. There was nearly 90% suppression of erythroid colony-forming unit expression and 60% suppression of erythroid burst-forming unit expression at 2:1 T cell to bone marrow ratios and somewhat less suppression at 1:1. Granulocyte/macrophage progenitor expression was unaffected. Erythroid progenitor differentiation in the marrows of two HLA identical siblings was similarly suppressed. The cells were co-cultured with the marrows of nine nonrelated donors to investigate the potential genetic restriction of this suppression. Colony suppression equal to that observed in the marrow of the patient and his siblings was found in studies of two partially HLA identical individuals. No suppression was detected in marrow co-cultures of two entirely HLA dissimilar individuals. These results show that suppression of erythropoiesis by a unique subset of T8, Mo1, Ia-positive lymphocytes isolated from a patient with lymphocytosis and erythrocyte aplasia is genetically restricted.

Adult↗
PubMed1983

Thy-1 antigen in murine hematopoietic progenitor differentiation.

Until recently, the presence of Thy-1 antigen was thought to identify thymus-derived lymphocytes as opposed to other lymphohematopoietic cells. With the use of a highly amplified immunofluorescence assay and a monoclonal anti-Thy-1 antibody, the Thy-1 antigen has been detected on CFU-S. To determine the role of Thy-1 antigen in the differentiation of more committed hematopoietic progenitors, murine bone marrow was treated with anti-Thy-1.2 antibody and complement and cultured. Growth of erythroid burst-forming units (BFU-E) and granulocyte/macrophage colony-forming units (CFU-G/M) was greatly reduced following antibody and complement treatment and could not be restored with mitogen-stimulated spleen cell supernatants, splenic T cells, or thymocytes. These data demonstrate that a Thy-1.2-bearing cell is important in differentiation of early murine hematopoietic progenitors and they provide evidence that anti-Thy-1.2 antibody and complement treatment removes Thy-1.2 antigen-bearing hematopoietic progenitors. In contrast, growth of the macrophage progenitor (CFU-M) stimulated by L cell-conditioned media and the more mature erythroid colony-forming unit (CFU-E) was unaffected by anti-Thy-1.2 antibody and complement treatment. Therefore, Thy-1.2 antigen is not present on these progenitors. These data suggest that Thy-1.2 antigen is a differentiation antigen that is present on early murine hematopoietic progenitors and is lost as they differentiate.

Animals↗
PubMed1983

Evidence for a clonal model for hemoglobin switching.

The ontogenic switch from fetal to adult hemoglobin could be due to gradual replacement of fetal by adult erythroid progenitor cells, each with unique potential hemoglobin expression programs. We have studied globin synthesis in single colonies derived from the BFU-E of human newborn infants and rhesus monkey fetuses, both at the time of the switch. In the 140-day rhesus fetal colonies, beta synthesis ranged from 8% to 44% of (beta + gamma) in 47 colonies. When fetal colonies were arbitrarily defined as those with below 26% beta, and adult colonies those with above 26% beta, we predicted that there would be 12 adult colonies; 14 were observed. The rhesus fetal results were compatible with the presence of two or more classes of progenitors within the population seen at the time of the switch. In the human newborn study, the number of colonies increased fourfold from day 14 to day 21 in culture. beta synthesis also increased. These increases occurred even in cultures from which red, well-hemoglobinized colonies were completely removed as they appeared. New cohorts of late-appearing colonies were derived from immature progenitors. The early colonies showed correlation of G gamma and beta synthesis, but the late colonies did not show this correlation. We had found the latter pattern previously in adult, fetal-like colonies. Thus fetal progenitors in man have high levels of Hb F and G gamma, with correlation of these parameters at the level of single-progenitor-derived colonies; these fetal progenitors are found in fetuses and newborns. Adult, fetal-like progenitors have lower levels of Hb F and G gamma, without any correlation between the levels of each. The adult progenitors appear in newborn infants as the switch occurs, and they are the only class found in adults. Our observations in the simian and human studies support a clonal model for hemoglobin switching.

Animals↗
PubMed1983

Elimination of leukemic cells from human bone marrow using monoclonal antibody and complement.

Human leukemic cells which bear the common acute lymphoblastic leukemia antigen can be lysed with a murine monoclonal antibody (J-5) in the presence of rabbit complement. Conditions have been defined for eliminating 51Cr-labeled common acute lymphoblastic leukemia antigen-positive NALM-1 cells or cryopreserved leukemic lymphoblasts from a 100-fold excess of human bone marrow. Optimal lysis is obtained with treatment for a total of 90 min. Three treatments for 30 min are more effective than two treatments for 45 min or one treatment for 90 min. Separation of marrow on a Ficoll:diatrizoate gradient does not permit more effective elimination of leukemic cells. Tumor cell lysis is inhibited by high concentrations of common acute lymphoblastic leukemia antigen-positive cells (2 X 10(7)/ml) and by high concentrations of bone marrow (10(8)/ml). Under optimal conditions, greater than 99% of 51Cr-labeled leukemic lymphoblasts can be eliminated from a 100-fold excess of human marrow. Selective removal of leukemic cells from human bone marrow in vitro should facilitate trials of autologous marrow transplantation.

Antibodies, Monoclonal↗
PubMed1982

Autologous bone-marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in-vitro treatment with J5 monoclonal antibody and complement.

A monoclonal antibody (J5) specific for the common acute-lymphoblastic-leukaemia antigen (CALLA) was used for in-vitro pre-treatment of bone-marrow before autologous transplantation in four patients with CALLA-positive acute lymphoblastic leukaemia (ALL) in relapse, who did not have HLA-compatible donors. After remission induction and intensification, bone-marrow cells were harvested, treated with J5 antibody and rabbit complement, and cryopreserved in liquid nitrogen. Patients received ablative chemotherapy and total-body irradiation before reinfusion of autologous J5-treated bone marrow. The transplantation protocol was well tolerated, and engraftment of normal myeloid cells occurred in all for patients. Two patients have continued in unmaintained remission with complete haematopoietic reconstitution for more than 1 year after autologous transplantation.

Antibodies, Monoclonal↗
PubMed1982

Effect of acyclovir and interferon on human hematopoietic progenitor cells.

Continuous in vitro exposure of human bone marrow cells to acyclovir (approximately 200 microM) or human leukocyte interferon (approximately 250 U/ml) caused 50% inhibition of granulocyte colony-forming cell differentiation. Colonies expressed in the presence of either agent were reduced both in size and number. Erythroid progenitors were more resistant than granulocyte progenitors to the antiproliferative effects of acyclovir. Progenitor cells of patients recovering from cytotoxic chemotherapy were no more sensitive to the effects of acyclovir or interferon than were cells obtained from patients before chemotherapy.

Acyclovir↗
PubMed1982

Synthesis of hemoglobin F in adult simian erythroid progenitor-derived colonies.

The simian hematopoietic system is known to respond to anemic stress with the production of erythrocytes containing large amounts of fetal hemoglobin. To determine the regulatory mechanism responsible for hemoglobin F (HbF) production in stress erythropoiesis, adult simian bone marrow cells were cultured in plasma clots in the presence or absence of erythropoietin and burst-promoting activities, and the HbF content of progenitor-derived colonies was determined by radioimmunoligand assay. Three classes of erythroid progenitors were detected: BFU-E, CFU-E, and a very mature cohort of dense highly erythropoietin-responsive cells (HERC). These classes varied in inverse proportion to their maturity with respect to their potential for HbF accumulation in the colonies to which they give rise. Both erythropoietin and burst-promoting activity stimulated HbF production, particularly in colonies derived from immature progenitors. For example, under conditions of high erythropoietin stimulation, BFU-E colonies contained 13.7-37.7% HbF, CFU-E colonies contained 2.8-13.5% HbF, and HERC colonies 0-1% HbF. These results suggest that under nonstress conditions simian erythrocytes are derived almost entirely from HERC progenitors and proerythroblasts in which gamma chain synthesis is suppressed. During stress erythropoiesis, augmented HbF accumulation could be explained by the rapid entrance into the marrow of proerythroblasts directly derived from immature progenitors. Gamma chain production in these proerythroblasts is additionally regulated by the changes in environmental erythropoietin and burst-promoting activities.

Animals↗
PubMed1982

Biological activity, lipoprotein-binding behavior, and in vivo disposition of extracted and native forms of Salmonella typhimurium lipopolysaccharides.

Although phenol-extracted gram-negative bacterial lipopolysaccharides (LPS) have been used to study the properties of endotoxins for many years, nothing is known about the behavior of native (unextracted) LPS in vivo. Accordingly, we have compared extracted and native forms of LPS with regard to their biological activity, their ability to bind to plasma high density lipoproteins (HDL), and their fate after intravenous injection into rats. The LPS of Salmonella typhimurium G-30 were labeled with [(3)H]galactose, and whole bacteria, bacterial outer membranes, outer membrane fragments (harvested from the bacterial culture supernatant), and phenol extracts of the bacteria were prepared. After defining the LPS, phospholipid, and protein composition of these preparations, we compared the activity of the LPS in phenol extracts and membrane fragments in two assays. In both the limulus lysate assay and the rabbit pyrogen test, the LPS in phenol extracts were slightly more potent than the LPS in membrane fragments. We next studied the ability of the LPS in each preparation to bind to rat lipoproteins in vitro, and each preparation was then injected intravenously into rats for measurements of LPS-HDL binding and tissue uptake in vivo. Two patterns of lipoprotein binding were observed. Less than 25% of the LPS in both outer membranes and whole bacteria bound to HDL in vitro. When the outer membranes and whole bacteria were injected into rats, their LPS again bound poorly to HDL and they were rapidly removed from plasma into the liver and spleen. In contrast, >50% of the LPS in both culture supernatant membrane fragments and phenol-water extracts bound to HDL in vitro. When these preparations were injected into rats, approximately 50% of the LPS in the membrane fragments and phenol-water extracts bound to HDL and remained in the plasma over the 10-min study period. Moreover, the LPS in these preparations accumulated in the ovary and the adrenal gland, two tissues that use HDL-cholesterol for hormone synthesis. Binding to HDL thus greatly influenced the plasma half-life and tissue uptake of both extracted and native LPS. We conclude that extraction of S. typhimurium LPS with phenol does not significantly alter the biological activity or the lipoprotein binding behavior of the LPS and that the in vivo fates of phenol-extracted and membrane fragment LPS are essentially identical. The results thus provide important support for many previous studies that have used phenol-extracted LPS to mimic the activities of native LPS in vivo. However, the only native LPS that resembled the behavior of extracted LPS were the LPS that had been shed from the bacteria in fragments of membrane that had reduced amounts of protein and phospholipid. Removal of LPS from other outer membrane constituents, whether by chemical extraction or by a natural process of surface shedding, thus alters the behavior of the LPS; the most important feature of this alteration appears to be the ability of these LPS to bind readily to HDL.

Adrenal Glands↗
PubMed1982

Clinical pharmacology of 9-beta-D-arabinofuranosyladenine in combination with 2'-deoxycoformycin.

It has been suggested that, by inhibiting the adenosine deaminase (ADA)-mediated catabolism of 9-beta-D-arabinofuranosyladenine (ara-A), 2'-deoxycoformycin (DCF) would increase the half-life (t1/2) of ara-A, a compound with known antileukemic activity. To test this hypothesis, we collected serial plasma samples from five patients with refractory acute lymphoblastic leukemia who participated in a Phase I trial of i.v. DCF 915 mg/sq m) in combination with i.v. single-dose ara-A (120-250 mg/sq m). In four of these patients, of whom three were known to have achieved greater than 98% ADA inhibition, a mean ara-A t1/2 of 227 min was achieved. Extrapolated peak levels (i.e., following infusion of ara-A) ranged from 1.5 to 7.4 micrograms/ml (mean, 4.2 micrograms/ml). Elimination of drug appeared to follow a single-compartment model. In two patients who received ara-A without prior DCF and in a third patient who had significant residual ADA activity despite DCF, ara-A was unmeasurable within 5 min of the end of infusion. These data confirm that the kinetics of ara-A catabolism can be altered by inhibition of ADA and suggest that more than one dose of DCF may be necessary for complete inhibition of the enzyme and optimal pharmacological modulation of ara-A.

Adolescent↗
PubMed1981

Histiocytosis-X.

Twelve of 17 patients with histiocytosis-X were immunologically abnormal, as shown by the presence of circulating lymphocytes spontaneously cytotoxic to cultured human fibroblasts or of antibody to autologous erythrocytes. The patients also had a notable lack of histamine H2 surface receptors on their T lymphocytes, suggesting a suppressor-cell deficiency. The lymphocyte abnormalities were reversed in vitro after incubation in a crude extract of calf thymus gland, and therefore all 17 patients were treated with daily intramuscular injections of this extract. With this therapy, 10 patients entered complete remission -- a response at least as good as that observed in historical controls treated with chemotherapy. A positive clinical response was associated with an increase in the number of T-cell histamine H2 receptors to normal levels and with correction of the other immunologic abnormalities. The results of this preliminary study justify a larger prospective clinical trial of thymic extract and further investigation of the immunoregulatory mechanisms in histiocytosis-X.

Cell Membrane↗