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Biomedical subjects

J M Lipton

Publications and source records attributed to J M Lipton.

At least 91 records · Page 5Linked to original sources
PubMed1991

Inhibition of acute inflammation in the periphery by central action of salicylates.

Understanding of the antiinflammatory actions of nonsteroidal drugs is incomplete, but these actions are believed to occur in the periphery, without any contribution from the central nervous system. Recent research on the antipyretic antiinflammatory neuropeptide alpha-melanocyte-stimulating hormone indicates that it can act centrally to inhibit peripheral inflammation; this raises the possibility that other agents, such as nonsteroidal antiinflammatory drugs, may have similar activity. In the present research both lysine acetylsalicylate and sodium salicylate inhibited edema, induced in the mouse ear by topical application of picryl chloride, when injected into the lateral cerebral ventricle. This inhibitory activity on a measure of acute inflammation was not due to escape of the drugs into the periphery, because systemic injection of doses that were effective centrally did not affect inflammation. In contrast, central administration of a dose of indomethacin that was antiinflammatory when given intraperitoneally did not inhibit peripheral inflammation. Thus indomethacin apparently lacks the central antiinflammatory action of the salicylates. This observation, plus our inability to demonstrate either an antiinflammatory effect of intracerebroventricular dexamethasone, a prostaglandin inhibitor, or a pro-inflammatory influence of prostaglandin E2, suggests that prostaglandins are not important to central modulation of inflammation. The results indicate that, in addition to having central influences on fever and pain, salicylates can act within the brain to inhibit acute inflammation in the periphery.

Animals↗
PubMed1991

Expression of intercellular adhesion molecule-1 (CD54) on hematopoietic progenitors.

The distribution of intercellular adhesion molecule-1 (ICAM-1), a ligand for lymphocyte function antigen-1, on hematopoietic tissue was determined using the anti-ICAM-1 monoclonal antibody CL203.4 with flow cytometry and short-term semi-solid hematopoietic progenitor cultures. After timed incubation in media with fetal bovine serum, 29% of erythroid burst-forming units (BFU-E), 24% of erythroid colony-forming units (CFU-E), and 52% of granulocyte-macrophage colony-forming units (CFU-GM) bone marrow progenitors expressed ICAM-1. This finding, which is consistent with the detection of ICAM-1 on acute non-lymphoblastic leukemic blasts, is at variance with recent reports. ICAM-1 was also detected on bone marrow blasts, proerythroblasts, promyelocytes, and cells of monocyte/macrophage lineage, but was not detected on erythroblasts, normoblasts, neutrophilic myelocytes, metamyelocytes, bands, or on most lymphocytes. These results indicate that maturation of cells of the erythroid and myeloid lineage is associated with loss of ICAM-1. The distribution of ICAM-1 on bone marrow progenitors, early precursor cells, and accessory cells in conjunction with the function of this molecule in cell-cell interactions suggests that ICAM-1 may play a role in the cell-cell and cell-stromal interactions that regulate hematopoiesis.

Antibodies, Monoclonal↗
PubMed1991

Dexamethasone facilitates release of the neuropeptide alpha-MSH.

alpha-Melanocyte stimulating hormone (alpha-MSH) has important host defense properties, in part similar to those of corticosteroids. Previous research suggests that secretion of alpha-MSH and of ACTH are controlled separately. The relationship between release of alpha-MSH and the activity of the hypothalamic-pituitary-adrenal axis in the rabbit was examined by monitoring changes in circulating alpha-MSH, ACTH, and corticosterone in response to endotoxin and corticotropin-releasing hormone (CRH), both with and without dexamethasone pretreatment. Endotoxin (1 microgram/kg IV) did not cause alpha-MSH release, but it did increase plasma concentrations of ACTH and corticosterone. Similarly, CRH (1 and 10 micrograms/kg IV) did not affect plasma alpha-MSH, whereas it stimulated ACTH and corticosterone release. Dexamethasone pretreatment abolished the responses of ACTH and corticosterone to either stimulus and did not modify circulating alpha-MSH after CRH. In contrast, dexamethasone pretreatment did result in a significant increase in plasma alpha-MSH after a dose of endotoxin that was ineffective alone. These data indicate that corticosteroids can facilitate the release of alpha-MSH, a powerful anti-inflammatory hormone. Since corticosteroids are released with certain challenges, this facilitatory activity may be important to the host response.

Adrenocorticotropic Hormone↗
PubMed1990

Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation.

A 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure was treated with high-dose cyclophosphamide, busulfan, and antithymocyte globulin followed by an infusion of human leukocyte antigen-identical, mixed lymphocyte culture (MLC) non-reactive sibling bone marrow. He developed cardiac arrhythmias and intractable hypotension and died on day 23 posttransplant. Autopsy findings were consistent with cyclophosphamide-induced pancarditis. The bone marrow showed signs of early engraftment. Allogeneic bone marrow transplantation may be a treatment alternative for Shwachman-Diamond syndrome with severe bone marrow failure. However, fatal posttransplant pancarditis due to doses of cyclophosphamide not usually associated with cardiac death may be an unanticipated problem. Further trials of bone marrow transplantation as therapy for this syndrome may be warranted, perhaps using lower doses of cyclophosphamide or substituting for it other immunosuppressive and myelosuppressive agents.

Bone Marrow Diseases↗
PubMed1990

Acute phase response to endotoxin: rise in plasma alpha-MSH and effects of alpha-MSH injection.

Endotoxins, cell wall components of bacteria, cause a number of biological effects, presumably via induction of potent cytokines. Previous research suggests that the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and its COOH-terminal tripeptide reduce the effects of cytokines. These molecules evoke antipyretic and anti-inflammatory effects in vivo. Localization of alpha-MSH within lymphocytes and recent observations that alpha-MSH receptors are widespread and that circulating alpha-MSH increases after systemic injection of endogenous pyrogen, a cytokine-containing extract, suggest that the peptide modulates host defense reactions. One aim of the present experiments was to learn whether a rise in circulating alpha-MSH occurs in synchrony with aspects of the acute phase response (APR) in conscious rabbits given endotoxin. A second aim was to learn whether administration of a single large dose of alpha-MSH inhibits all aspects of the APR induced by a low dose of endotoxin. The results indicate that the concentration of circulating alpha-MSH in rabbits does increase along with other changes in the APR (e.g., increase in corticosterone), which suggests that the peptide is widely available to modulate cytokine effects after endotoxin. Contrary to expectations based on previous results, a large dose of the peptide given intravenously inhibited only fever and not other aspects of the APR. The results suggest that the rise in circulating alpha-MSH is an aspect of the APR and that an acute increase in the circulating peptide caused by intravenous injection does not inhibit all other aspects of the host response to endotoxin.

Acute-Phase Reaction↗
PubMed1990

Esmolol attenuates cardiovascular responses to extubation.

Changes in heart rate and systolic blood pressure were measured during extubation and emergence from anesthesia in 40 ASA physical status I and II patients in a double-blind study to assess the effect of three doses of esmolol (1, 1.5, and 2 mg/kg) given as a bolus 2 min after reversal of neuromuscular blockade. Heart rate (P less than 0.01), systolic blood pressure (P less than 0.02), and rate-pressure product (P less than 0.01) increased significantly during extubation of the control group. All doses of esmolol attenuated the increases in heart rate, but 1 mg/kg was insufficient to control the increase in systolic blood pressure. Doses of 1.5 and 2 mg/kg controlled both systolic blood pressure and heart rate, but the larger dose produced significant decreases in systolic blood pressure.

Adolescent↗
PubMed1989

Antipyretic effect of central alpha-MSH summates with that of acetaminophen or ibuprofen.

The neuropeptide alpha-melanocyte stimulating hormone has potent antipyretic properties when given centrally or systemically. Little is known about the mechanism of the antipyretic action and virtually nothing is known about interactions among the antipyretic effects of alpha-MSH and commonly used antipyretic agents. Randomized studies in which alpha-MSH, acetaminophen or ibuprofen, or a combination of alpha-MSH and antipyretic drug, were given IV to rabbits made febrile by endogenous pyrogen, indicate that the antipyretic effect of the peptide is summative with those of the drugs. alpha-MSH has been shown to have a wide safety margin in earlier research and the results suggest that combinations of peptide and antipyretic drugs might be safer and have fewer side effects than larger quantities of the drugs alone.

Acetaminophen↗
PubMed1989

An intrinsic progenitor defect in Diamond-Blackfan anaemia.

To determine whether the erythropoietin (epo) insensitivity of erythroid progenitor differentiation in congenital pure red cell aplasia or Diamond-Blackfan anaemia is intrinsic to the progenitor itself or is due to defective accessory cell function or active suppression, progenitors from normals and two patients (one steroid resistant and one spontaneously remitting), separated from all known accessory cells using sequential negative selection techniques (adherence, E-rosetting, and direct and indirect immune-panning), were studied. Initially, we evaluated three patients with DBA using unfractionated bone marrow mononuclear cells. Progenitors from two steroid non-responsive patients showed insensitivity to crude epo (c-epo) while one steroid responsive patient demonstrated normal in vitro sensitivity to c-epo. When recombinant epo (r-epo) was used in place of c-epo, the two steroid non-responders continued to demonstrate in vitro progenitor epo insensitivity. However, sensitivity of progenitors from the steroid responder, which was normal in the presence of c-epo, became abnormal when recombinant epo (r-epo) was substituted. Thus, using unfractionated bone marrow, the abnormal response to epo of progenitors from some patients with DBA appears to be obscured by stimulating factors termed erythroid burst-promoting activity (BPA) which are present in c-epo. Using fractionated highly enriched progenitors, from normals and a steroid responsive patient a final 3-10-fold enrichment of progenitors was achieved, but no such enrichment was seen when marrow from a steroid resistant patient was cultured. The epo sensitivities of normal and of patient erythroid progenitors were similar. However, at sub-optimal epo concentrations in both patients CFU-E responsiveness to crude BPA was abnormal compared to the three controls. We conclude from these studies that in DBA: (a) the failure of erythropoiesis is due to an intrinsic progenitor defect; (b) this defect involves progenitor insensitivity to factors in addition to erythropoietin: and (c) there exists a spectrum of disease reflected in the degree of the in vitro abnormality observed.

Adolescent↗
PubMed1989

Acute-phase response to endogenous pyrogen in rabbit: effects of age and route of administration.

Aspects of host defense, collectively called the acute phase response (APR), can be induced by central actions of cytokines. To determine whether aging alters this response, aged and young rabbits were given endogenous pyrogen (EP), a crude preparation containing interleukin 1 and other cytokines, via an intracerebroventricular cannula. Arterial blood was sampled before EP administration and 2, 4, and 24 h later. Measurements were made of changes in body temperature, white blood cells, neutrophils, concentration of antipyretic, anti-inflammatory peptide alpha-melanocyte stimulating hormone (alpha-MSH), corticosterone, and C-reactive protein (CRP) concentrations. EP caused greater fever and increases in corticosterone and CRP in young rabbits. EP-induced changes in circulating neutrophils did not show age-related differences. There was no significant change in alpha-MSH in either age group; thus only certain aspects of APR induced by central actions of EP were altered with aging. To determine whether changes in APR caused by peripherally administered cytokines are similar to those after central injection, young female rabbits were given EP by both routes. Although administration caused greater fever, increases in alpha-MSH and corticosterone concentrations and in neutrophil counts were greater after intravenous administration, perhaps the result of a combined influence on peripheral and central receptors. The EP-induced increase in circulating alpha-MSH is a new finding that indicates that this antipyretic and anti-inflammatory peptide is rapidly available to modulate host responses after challenge.

Acute-Phase Reaction↗
PubMed1989

Age- and sex-related differences in febrile response to peripheral pyrogens in the rabbit.

A reduced febrile response with aging has been reported in mice, rats, rabbits, squirrel monkeys and man. Young adult male and female rats and rabbits respond differently to pyrogens, but little is known about relative febrile responses in old male and female animals. To further describe the effects of age and sex on fever, we gave intravenous injections of Salmonella typhosa endotoxin (0.05 micrograms/kg) and of endogenous pyrogen (EP) (40 microliters/kg) to old and young, male and female rabbits. Old females did not exhibit smaller fevers in response to endotoxin compared to young females, but both young and old females had smaller fevers than aged and young males. Old male rabbits did not have a decreased febrile response to endotoxin. Old females, but not old males, showed a reduced febrile response to EP, the presumed endogenous mediator of endotoxin fever, when compared to young rabbits. To determine if the reduced febrile responses were due to reduced capacity to generate heat, D-amphetamine sulfate (2 or 5 mg/kg i.v.) was administered, and the resulting hyperthermias indicated that all groups of rabbits, including the aged and young females, were capable of raising body temperature to high levels. Body weight and reduced capacity to produce and retain heat do not contribute to these differences in fever. We conclude that the febrile response is not uniform over age, and that it is also strongly influenced by sex and type of pyrogen.

Age Factors↗
PubMed1989

Autologous bone marrow transplantation for acute lymphoblastic leukemia.

Forty-four children with acute lymphoblastic leukemia (ALL) who had relapsed (N = 43) or had refractory disease (N = 1) were intensively treated with combination chemotherapy, had remission bone marrow (BM) harvested and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens, underwent postharvest ablative chemotherapy and radiotherapy and subsequently were infused with their autologous marrow. Of the 44 patients treated between November 1980 and January 1988, 19 relapsed, 10 died of complications, and 15 remained in complete remission for a median of 28.5 months (range, 10+ to 94+). Event-free survival (EFS) (+/- SE) at 5 years after autologous transplantation was 29 +/- 8%. For the 26 patients whose initial remission was greater than 2 years, event-free survival was 51 +/- 10%. These results compare favorably with allogeneic transplantation and chemotherapy trials for patients with relapsed ALL, and provide an alternative transplantation option for children without histocompatible donors.

Adolescent↗
PubMed1989

Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH.

The endogenous neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH 1-13), previously found to have marked antipyretic activity, inhibits histamine-induced increases in vasopermeability. The primary antipyretic amino acid message sequence is believed to be the COOH-terminal trieptide, lysine-proline-valine. In recent preliminary research this tripeptide inhibited increases in vasopermeability, raising the possibility that this portion of the alpha-MSH molecule has general antiinflammatory activity. To test this idea, the effects of graded doses of alpha-MSH [11-13] on ear swelling induced by picryl chloride in mice were compared with the effects of saline and a large dose of corticosteroid. Alpha-MSH [11-13] inhibited swelling in a dose-related fashion. This result, together with previous findings, suggests that endogenous circulating alpha-MSH and its COOH-terminal fragments may contribute to modulation of physiological responses in host defense. If this is true, it may be possible to develop new peptide drugs or mimetics based on the tripeptide that are useful in treating inflammation.

Amino Acid Sequence↗
PubMed1988

Thrombocytopenia with absent radii. A review of 100 cases.

The syndrome of thrombocytopenia with absent radii (TAR) is a rare congenital syndrome in which the characteristic hematological findings are hypomegakaryocytic thrombocytopenia, periodic leukemoid reactions, and eosinophilia. The thrombocytopenia usually presents at birth or during the neonatal period and may be profound, accounting for significant morbidity. However, resolution of the thrombocytopenia usually occurs after the first year. In this review of 100 cases, the clinical manifestations, pathophysiology, genetics, and treatment are discussed in detail. With the increased understanding of the natural history and pathophysiology of the hypomegakaryocytic thrombocytopenia in the TAR syndrome, in conjunction with the advances in supportive therapy discussed, the outlook for patients with this syndrome has become quite good.

Bone and Bones↗
PubMed1988

C-reactive protein, leukocytes, and fever after central IL 1 and alpha-MSH in aged rabbits.

Aged and young unanesthetized rabbits with intracerebroventricular cannulas were tested in experiments designed to determine whether increases in plasma C-reactive protein (CRP) level and leukocytosis can be rapidly induced by central administration of crude buffy-coat supernatant commonly called endogenous pyrogen or interleukin 1 (IL 1). The results indicate that both acute-phase responses occur during fever caused by central administration of this supernatant and that they are generally detectable within 2 h. Although the febrile response was smaller in aged female rabbits, there was no decline in CRP or leukocyte responses, an observation that was not predicted. The antipyretic neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) reduced fever caused by central IL 1 more effectively in the aged rabbits. alpha-MSH likewise inhibited the CRP and leukocyte responses to central IL 1. The results confirm that CRP and leukocyte responses can be driven by a central IL 1 signal and further indicate that the response can occur rapidly, consistent with direct central nervous system control of the acute-phase responses. The findings indicate that the acute-phase responses depend in part on the age of the host and that the responses can be modulated by an endogenous central nervous system peptide with known antipyretic and immune modulatory properties.

Acute-Phase Reaction↗
PubMed1987

Eugenol: antipyretic activity in rabbits.

The analgesic agent eugenol reduced fever when given intravenously in small doses to rabbits made febrile by interleukin 1. To test this observation further, the drug was given intragastrically and its antipyretic effect was compared with that of a molar equivalent dose of acetaminophen. Eugenol was more effective in reducing fever than acetaminophen. Tests with intracerebroventricular injections indicated that eugenol could act centrally to reduce fever in doses much smaller than those which were effective peripherally. Other tests with the presumed fever mediators sodium archidonate and prostaglandin E2 (PGE2), suggest that the central action of eugenol is similar to that of acetaminophen. Eugenol, a derivative of clove oil, has marked antipyretic activity when given intravenously, intragastrically and centrally and may reduce fever primarily through a central action that is similar to that of common antipyretic drugs such as acetaminophen.

Acetaminophen↗
PubMed1987

Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits.

alpha-MSH within the septal region of the brain has been implicated in fever control; this peptide and ACTH (1-24), which contains the alpha-MSH amino acid sequence, reduce fever when given intracerebroventricularly (ICV) or peripherally. These peptides also cause hypothermia when given in doses larger than those required to reduce fever. Both peptides occur naturally within the preoptic PO region of the brain, the CNS locus of primary temperature control. alpha-MSH (350 ng) injected bilaterally into the PO region via chronic cannulas reduced fever caused in six rabbits by IV injection of IL-1 (interleukin 1, endogenous or leukocyte pyrogen) but had no effect in afebrile animals. A larger dose (1.5 micrograms) not only reduced fever but caused hypothermia in 12 rabbits. In separate experiments PO injections of ACTH (1-24) (1 microgram) reduced normal temperature. In the same six rabbits alpha-MSH (1 microgram) caused slightly smaller hypothermia. alpha-MSH (1.5 micrograms) also had no effect in 8 afebrile rabbits when injected into the septum. The primary conclusion is that alpha-MSH receptors within the PO region can contribute to both the antipyretic and hypothermic actions that are observed after ICV and peripheral administration of the peptide.

Animals↗