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Biomedical subjects

J M Lipton

Publications and source records attributed to J M Lipton.

At least 55 records · Page 3Linked to original sources
PubMed1998

Use of the bispectrum to analyse properties of the human electrocardiograph.

The bispectrum and bicoherence spectrum have been shown to be powerful techniques for identifying different types of nonlinear system responses. This paper presents an introduction to bispectral techniques applied to biomedical signals and examines the bispectral properties of the human electrocardiograph (ECG). The bispectrum proves to be an effective tool for representing and distinguishing different ECG response types. Bispectral ECG analysis is non-invasive and may prove to be a useful discriminant diagnostic.

Electrocardiography↗
PubMed1997

alpha-MSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation.

Tumor necrosis factor (TNF-alpha) underlies pathological processes and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide alpha-MSH modulates actions and production of proinflammatory cytokines including TNF-alpha, but there is no prior evidence that it alters TNF-alpha induced within the brain. To test for this potential influence of the peptide, TNF-alpha was induced centrally by local injection of bacterial lipopolysaccharide (LPS). alpha-MSH given once i.c.v. with LPS challenge, twice daily intraperitoneally (i.p.) for 5 d between central LPS injections, or both i.p. and centrally, inhibited production of TNF-alpha within brain tissue. Inhibition of TNF-alpha protein formation by alpha-MSH was confirmed by inhibition of TNF-alpha mRNA. Plasma TNF-alpha concentration was elevated markedly after central LPS, indicative of an augmented peripheral host response induced by the CNS signal. The increase was inhibited by alpha-MSH treatments, in relation to inhibition of central TNF-alpha. Presence within normal mouse brain of mRNA for the alpha-MSH receptor MC-1 suggests that the inhibitory effects of alpha-MSH on brain and plasma TNF-alpha might be mediated by this receptor subtype. The inhibitory effect of alpha-MSH on brain TNF-alpha did not depend on circulating factors because the effect also occurred in brain tissue in vitro. This indicates that alpha-MSH can act directly on brain cells to inhibit their production of TNF-alpha. If central TNF-alpha contributes to pathology in CNS disease and injury, and promotes inflammation in the periphery, agents that act on brain alpha-MSH receptors should decrease the pathological TNF-alpha reaction and promote tissue survival.

Animals↗
PubMed1997

Anti-inflammatory actions of the neuroimmunomodulator alpha-MSH.

alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuroimmunomodulatory peptide that inhibits fever and all major forms of experimental inflammation. In humans, concentrations of alpha-MSH are increased at sites of inflammation, and in plasma in inflammatory disorders and after infection of endotoxin. The effects of this 'anti-cytokine' peptide are mediated through alpha-MSH receptors and regulatory circuits in macrophages and neutrophils, and through descending neural anti-inflammatory pathways that originate from alpha-MSH receptors on neurons within the brain.

Animals↗
PubMed1997

alpha-MSH modulates experimental inflammatory bowel disease.

The mechanisms underlying inflammatory bowel disease (IBD) remain obscure but the importance of inflammatory processes is clear and most pharmacological therapies inhibit inflammation. The search for more effective agents with low toxicity continues. To test the possibility that the antiinflammatory/anticytokine peptide alpha-MSH can be used to control IBD, the peptide was administered to a murine colitis model. The peptide treatment had marked salutary effects: it reduced the appearance of fecal blood by over 80%, inhibited weight loss, and prevented disintegration of the general condition of the animals. Mice given alpha-MSH showed markedly lower production of TNF alpha by tissues of the lower colon stimulated with concanavalin A; the inhibitory effect of alpha-MSH on production of inflammatory nitric oxide by lower bowel tissue was even greater. The combined results indicate that alpha-MSH modulates experimental IBD, perhaps by inhibiting production within the gut of the local proinflammatory agents TNF alpha and nitric oxide, or by inhibiting inflammatory processes closely linked to these mediators.

Animals↗
PubMed1997

Disparate lympho-erythroid donor to recipient chimaerism in a beta(0)-thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment.

A 4-year-old girl with transfusion-dependent beta(0)-thalassaemia received an HLA-identical bone marrow transplant (BMT) from her beta(0)-thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post-BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU-E) was analysed. On days 1000 and 1130 post-BMT, 79% and 77% of colonies, respectively, synthesized beta-globin and therefore were of donor origin.

Bone Marrow Transplantation↗
PubMed1997

Cytokine antagonists in aged subjects and their relation with cellular immunity.

Host responses to infectious and inflammatory stimuli are altered with aging. Because cytokines and their antagonists are significant factors in these host responses, the present research on aged subjects was designed to investigate plasma concentrations of the cytokines interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) and those of their antagonists IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor (sTNFr). For this research, 122 apparently healthy aged subjects (79.6 +/- 5.8 yr), 39 aged individuals with documented urinary tract infections (UTIs) (81.6 +/- 6.3 yr), and 100 young controls (39.32 +/- 11.2 yr) were included. Plasma IL-1 beta, TNF alpha, IL-1ra, sTNFr (55 kDa), and neopterin were measured using enzyme-linked immunosorbent assay techniques. In subsets of normal aged subjects and UTI patients, we investigated relations between plasma concentrations of cytokine antagonists and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cells. The results show that plasma concentrations of both IL-1ra and sTNFr were greater in healthy aged subjects than in young controls. Plasma neopterin, a product of activated monocytes/macrophages, was likewise elevated in the aged. IL-1 and TNF were not detectable in the majority of plasma samples. There was a positive correlation between neopterin concentration and both IL-1ra and sTNFr. There was a significant negative correlation between plasma IL-1ra and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cell in healthy aged subjects. IL-1ra and sTNFr concentrations were significantly greater in patients with UTI than in the healthy aged subjects. In UTI patients IL-2 production in vitro was lower than in healthy subjects, but there was no significant correlation with IL-1ra in plasma. Therefore, plasma concentrations of cytokine antagonists are increased in plasma of apparently healthy aged subjects. Elevated concentrations of neopterin suggest that this increase can be traced to monocyte activation. The negative correlation between plasma IL-1ra and IL-2 production in vitro suggests that enhancement of this cytokine antagonist can contribute to immunodepression of aging. We propose that unapparent infections in aged subjects cause monocyte activation and release of cytokine antagonists. These cytokine antagonists reduce IL-2 production and the capability of T cells to proliferate, thereby inhibiting responses in the elderly.

Adult↗
PubMed1997

The protective effects of alpha-melanocyte stimulating hormone on canine brain stem ischemia.

OBJECTIVE: To evaluate the influence of alpha-melanocyte stimulating hormone (alpha-MSH), an anti-inflammatory antagonist of the production and action of proinflammatory cytokines, 26 dogs were divided into four groups and exposed to isolated, reversible brain stem ischemia in the presence or absence of alpha-MSH treatment. METHODS: Brain stem auditory evoked potentials (BAEPs) and regional cerebral blood flow were measured during ischemia and for 5 hours after reperfusion. Group I was composed of five dogs that underwent surgical preparation only. Group II was composed of seven dogs that were exposed to 20 minutes of ischemia without treatment. Group III was comprised of seven dogs exposed to 20 minutes of ischemia with alpha-MSH treatment before and during ischemia. Group IV was composed of seven dogs exposed to 20 minutes of brain stem ischemia with alpha-MSH treatment only during reperfusion. RESULTS: During the ischemic period, BAEPs were abolished in all animals within 10 minutes. With reperfusion, the BAEPs increased to approximately 36% of baseline in Group II dogs that received no treatment. However, this increase was approximately 63% in animals that received alpha-MSH both before and during ischemia (Group III). In Group IV dogs that received alpha-MSH only during reperfusion, BAEPs were increased approximately 10 to 14% more than in Group II during the late reperfusion period. CONCLUSION: The improved recovery of BAEPs in dogs treated with alpha-MSH suggests that this peptide may have neuroprotective effects in brain stem ischemia and reperfusion injury. This effect may be caused by an antagonistic action of alpha-MSH on cytokine-induced ischemic brain damage.

Animals↗
PubMed1996

alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line.

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.

Amino Acid Sequence↗
PubMed1996

The neuropeptide alpha-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro.

The proopiomelanocortin-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH) has potent anti-inflammatory effects in all animal models of inflammation against which it has been tested. Understanding of the mechanism by which this occurs is incomplete, although there is recent evidence for alpha-MSH receptors in murine and human macrophages and for modulation of production of proinflammatory cytokines and related mediators by alpha-MSH. Because of the prominence of neutrophils in early stages of inflammatory reactions where alpha-MSH is effective, we examined human neutrophils for evidence of mRNA for alpha-MSH receptors and for inhibition of neutrophil chemotaxis. There was accumulation of mRNA for melanocortin receptor 1 (MC1) in RT/PCR product from neutrophils stimulated with interferon and LPS. In subsequent studies alpha-MSH inhibited migration of neutrophils from most normal volunteers when the cells were placed in FMLP or IL-8 gradients. The inhibition by alpha-MSH could be traced to alterations in cAMP in neutrophils. The presence of alpha-MSH receptor message in neutrophils is consistent with the established anti-inflammatory effects of the peptide. Direct inhibition of neutrophil chemotaxis likely contributes to the anti-inflammatory activity of alpha-MSH.

Analysis of Variance↗
PubMed1996

Bone marrow failure in children.

Bone marrow failure in the pediatric patient places the hematologist at the junction of clinical medicine, cellular biology, and molecular genetics. The pathophysiology of these disorders is rapidly being elucidated in many laboratories. Treatments such as bone marrow transplantation and the nascent modality of gene therapy are firmly grounded in these modern sciences. This year's progress in the understanding, diagnosis, and treatment of a wide variety of predominantly pediatric bone marrow failure states is a direct result of the union between the "laboratory bench and the patient bedside."

Anemia, Aplastic↗
PubMed1995

Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of alpha-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We measured NO and alpha-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon gamma. alpha-MSH inhibited production of NO, as estimated from nitrite production and nitration of endogenous macrophage proteins. This occurred through inhibition of production of NO synthase II protein; steady-state NO synthase II mRNA abundance was also reduced. alpha-MSH increased cAMP accumulation in RAW cells, characteristic of alpha-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary alpha-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecular of alpha-MSH, was expressed in RAW cells, and tumor necrosis factor alpha increased production and release of alpha-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor alpha can induce macrophages to increase production of alpha-MSH, which then becomes available to act upon melanocortin receptors on the same cells. Such stimulation of melanocortin receptors could modulate inflammation by inhibiting the production of NO. The results suggest that alpha-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.

Amino Acid Oxidoreductases↗
PubMed1995

Endogenous cytokine antagonists during myocardial ischemia and thrombolytic therapy.

We tested the idea that cytokine antagonists are released during acute myocardial ischemia to counteract proinflammatory effects of cytokines. We investigated changes in plasma concentrations of the anticytokine molecules alpha-melanocyte-stimulating hormone (alpha-MSH), interleukin-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor (sTNFr) in patients with acute myocardial infarction (AMI) or unstable angina (UA). Blood samples were collected at presentation in the coronary care unit, at 3-hour intervals for 24 hours, and daily for 4 days thereafter. There were no significant differences in the concentrations of cytokine antagonists in patients with AMI or UA. However, whereas concentrations of alpha-MSH were increased in early samples of patients with AMI or UA who were treated with a thrombolytic agent, they were consistently low in untreated patients. IL-1ra concentrations likewise were greater 3 and 6 hours after treatment in patients who underwent thrombolysis, whereas there was no significant difference in plasma sTNFr between the two groups. We suggest that during myocardial ischemia and thrombolysis anticytokine molecules released from the injured myocardium become available to reduce inflammation caused by cytokines and other mediators of inflammation.

Adult↗
PubMed1995

Modulation of adhesion molecule CD54 expression on CD34+ hematopoietic progenitors.

Multiple cellular adhesion molecules are constitutively expressed on hematopoietic progenitors. CD54 (ICAM-1), a member of the immunoglobulin supergene family, has recently been shown to be present on a subset of hematopoietic progenitors. To demonstrate that this adhesion molecule is expressed on the surface of the hematopoietic progenitor following induction rather than in its basal state, we studied the expression of cell surface CD54 on flow-cytometric (FACS) gated progenitors (CD34+; lymph plus blast light scatter). A mean +/- standard deviation (SD) of 2.75 +/- 2.10% was seen for FACS-gated progenitors from freshly isolated bone marrow mononuclear cells (BMMNC) stained with anti-CD54 MAb. Following incubation at 37 degrees C for 20 to 22 hours in media supplemented with heat-inactivated bovine fetal serum (FBS), the percentage of FACS-gated progenitors staining with anti-CD54 MAb increased to 46.28 +/- 18.38. This increase was temperature and time dependent. The percentage of FACS-gated progenitors stained with anti-CD54 MAb did not increase following 20 to 22 hours of incubation at 4 degrees C. Furthermore, a subpopulation of FACS-gated progenitors staining with anti-CD54 MAb was detectable by 5 hours of incubation at 37 degrees C; the percentage of these progenitors staining with anti-CD54 MAb plateaued after 10 hours of timed incubation. Once induced, progenitor cell surface CD54 antigen density remained stable, as evidenced by a constant mean fluorescence intensity of anti-CD54 MAb staining. Three-color immunofluorescent studies showed that induction of CD54 occurred on CD45+ FACS-gated progenitors and that CD54 was induced on a subset of BMMNC expressing CD34 and CD11a, a counter receptor for CD54 that is limited in distribution to leukocytes. CD54 expression was induced to the same degree on FACS-gated progenitors positive or negative for CD19, CD36, and HLA-DR, respectively. These data indicate that CD54 is a unique adhesion molecule as its expression can be induced on CD34+ hematopoietic progenitors, and this induction does not appear to be related to hematopoietic progenitor lineage commitment or maturity.

Antigens, CD↗
PubMed1994

Elevation of plasma ACTH concentration in rabbits made febrile by systemic injection of bacterial endotoxin.

This study was carried out to investigate the adrenocorticotropic hormone (ACTH) response in rabbits made febrile by systemic injection of lipopolysaccharide (LPS, Salmonella typhosa endotoxin). Intravenous (i.v.) injection of LPS (0.1 microgram/kg and 1.0 microgram/kg) increased rectal temperature (biphasic fever) and the plasma concentration of ACTH (ACTH response) in a dose-related manner. These responses were suppressed by pretreatment with indomethacin (20 mg/kg, subcutaneously). Intracerebroventricular (i.c.v.) administration of indomethacin (400 micrograms) had no effect on the ACTH response to LPS, although it significantly suppressed febrile response. Small increases in plasma concentration of ACTH and significant fevers followed i.c.v. administration of prostaglandin E2 (2 micrograms) or F2 alpha (2 micrograms). I.v. administration of corticotropin releasing factor (CRF) antagonist [alpha-helical CRF (9-41) (200 micrograms/kg)] partly suppressed the ACTH increase induced in plasma by i.v. LPS. These results suggest that prostaglandins synthesized outside the blood-brain barrier play an important role in the ACTH response and that the mechanism for induction of the ACTH response is not exactly the same as that for the febrile response, although prostaglandins are involved in both responses.

Adrenocorticotropic Hormone↗
PubMed1994

Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis.

Programmed cell death, also known as apoptosis, is frequently initiated when cells are deprived of specific trophic factors. To investigate if accelerated apoptosis contributes to the pathogenesis of Diamond-Blackfan anemia (DBA), a rare pure red blood cell aplasia of childhood, we studied the effect of erythropoietin (epo) deprivation on erythroid progenitors and precursors from the bone marrow of DBA patients as compared with hematologically normal controls. Apoptosis in response to epo deprivation was evaluated by enumeration of colony-forming unit-erythroid (CFU-E)- and burst-forming unit-erythroid (BFU-E)-derived colonies in plasma clot semisolid culture and by the identification of typical DNA oligosomes by gel electrophoresis from marrow mononuclear cells in liquid culture. In all DBA patients there was a marked decrease in CFU-E- and BFU-E-derived colony formation compared with normal controls at comparable time points of epo deprivation, with a complete loss of CFU-E-derived colonies in semisolid culture by 9 hours of epo deprivation versus 48 hours in controls. The BFU-E-derived colony response to epo deprivation displayed a similar pattern of decrement. Apoptotic changes assessed by the presence of characteristic DNA fragmentation began in the absence of epo deprivation and were readily detected within 3 hours of epo deprivation in DBA cultures versus 9 hours in controls. We conclude that DBA is characterized by accelerated apoptosis as measured by the loss of erythroid progenitor clonogenicity and increased progenitor and precursor DNA fragmentation leading to the formation of characteristic oligosomes, consistent with an intrinsic erythroid-progenitor defect in which increased sensitivity to epo deprivation results in erythroid failure.

Adolescent↗