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Biomedical subjects

M Feldman

Publications and source records attributed to M Feldman.

At least 55 records · Page 3Linked to original sources
PubMed2000

Some views on the manifestation of the death instinct in clinical work.

The author argues that the postulation of the instinctual drive towards death can be seen as an attempt to account for the manifestation of a destructive psychological force that is palpably present in many of our patients. He discusses some of the experiences, activities and aims that reflect this destructive psychic force, and the conscious and unconscious gratification that is intrinsically bound up with it. What is 'deadly' is the way in which meaning, specificity and differences are attacked, and any developmental processes retarded or undermined. The vitality is taken out of the patient himself as well as his objects, and although in an important sense these drives are 'anti-life', the author suggests that their aim is not literally to kill or to annihilate, but that the patient feels compelled to maintain a link with the object that often has an evidently tormenting quality. Using a detailed clinical illustration, the author argues that the gratification that is bound up in these activities, and which gives them such a compulsive quality, does not result from fusion with the life instinct, with the resultant libidinisation of the death instinct. On the contrary, the gratification obtained from attacking, spoiling and undermining, whether directed to the self or the object, is an essential element of such a destructive drive.

Adult↗
PubMed1999

Immunogenicity of H-2Kb-low affinity, high affinity, and covalently-bound peptides in anti-tumor vaccination.

CTL induction by immunization with synthetic peptide epitopes has been shown to inhibit tumor growth and its metastatic spread. Ex vivo pulsing of peptides on MHC class I-bearing cells such as RMA-S cells or professional APCs elicits an effective CTL response. Since the stability of the MHC-peptide complex is strongly correlated with the overall immunogenecity, we compared the effect of immunization with low affinity, high affinity, and irreversibly bound MHC peptides in the context of immunotherapy of metastasis. MUT1, a tumor-associated antigen peptide that was isolated from 3LL Lewis lung carcinoma, is a low H-2Kb binder. MUT1 was modified into a high binder by changing positions 3, 5, and 8 to the favorable anchor residues. In addition, we introduced a photo-active chemical moiety, which can bind irreversibly to MHC upon illumination. These peptides, loaded onto RMA-S, were used to immunize mice against the 3LL tumor. Vaccination via the covalent conjugation of the low binder peptide was found to increase the CTL response measured against MUT1 loaded cells and against H-2Kb transfected D122 cells relative to the native MUT1 peptide. However, the photo cross-linking of the high affinity peptide to the MHC did not significantly improve the induction of specific CTL. The level of CTL activity was elevated to the same extent by either cross-linking the peptide to the MHC or by modifying it into a high-binder peptide. The protective capacity of all the peptide-based vaccines against D122 metastatic spread to the lungs was found to be comparable. These results indicate that augmentation of the affinity of a TAA peptide to the RMA-S surface MHC molecules, by conversion to a high-affinity mimotope or by photo-conjugation, can significantly enhance the immune response. There seems to be, however, a ceiling beyond which increase in the peptide-binding affinity does not lead to a corresponding enhancement of the overall immunogenicity of the peptide.

Animals↗
PubMed1999

Unique antiplatelet effects of a novel S-nitrosoderivative of a recombinant fragment of von Willebrand factor, AR545C: in vitro and ex vivo inhibition of platelet function.

The recombinant fragment of von Willebrand factor (vWF) spanning Ala444 to Asp730 and containing an Arg545Cys mutation (denoted AR545C) has antithrombotic properties that are principally a consequence of its ability to inhibit platelet adhesion to subendothelial matrix. Endothelial-derived nitric oxide (NO) can also inhibit platelet function, both as a consequence of inhibiting adhesion as well as activation and aggregation. Nitric oxide can react with thiol functional groups in the presence of oxygen to form S-nitrosothiols, which are naturally occurring NO derivatives that prolong the biological actions of NO. Because AR545C has a single free cysteine (Cys545), we attempted to synthesize the S-nitroso-derivative of AR545C and to characterize its antiplatelet effects. We successfully synthesized S-nitroso-AR545C and found that it contained 0.96 mol S-NO per mole peptide. S-nitroso-AR545C was approximately 5-fold more potent at inhibiting platelet agglutination than was the unmodified peptide (IC(50) = 0.02 +/- 0. 006 micromol/L v 0.1 +/- 0.03 micromol/L, P =.001). In addition and by contrast, S-nitroso-AR545C was a powerful inhibitor of adenosine diphosphate-induced platelet aggregation (IC(50) = 0.018 +/- 0.002 micromol/L), while AR545C had no effect on aggregation. These effects were confirmed in studies of adhesion to and aggregation on extracellular matrix under conditions of shear stress in a cone-plate viscometer, where 1.5 micromol/L S-nitroso-AR545C inhibited platelet adhesion by 83% and essentially completely inhibited aggregate formation, while the same concentration of AR545C inhibited platelet adhesion by 74% and had significantly lesser effect on aggregate formation on matrix (P </=.004 for each parameter by ANOVA). In an ex vivo rabbit model, we also found that S-nitroso-AR545C had a more marked and more durable inhibitory effect on botrocetin-induced platelet aggregation than did AR545C, and these differences were also reflected in the extent and duration of effect on the prolongation of the bleeding time in these animals. These data show that S-nitroso-AR545C has significant and unique antiplatelet effects, inhibiting both adhesion and aggregation, by blocking platelet GPIb receptor through the AR545C moiety and elevating platelet cyclic 3',5'-guanosine monophosphate through the -SNO moiety. These observations suggest that this NO-modified fragment of vWF may have potential therapeutic benefits as a unique antithrombotic agent.

Adult↗
PubMed1999

Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution.

Large clinical trials such as the second International Study of Infarct Survival routinely gave patients with myocardial infarction a chewed aspirin, yet there are no data to show whether chewing of aspirin is better, or worse, than swallowing a whole tablet. We performed a randomized, placebo-controlled study to determine whether chewing aspirin or administering it in solution accelerates its absorption and antiplatelet activity. On separate days, 12 fasting volunteers ingested 325 mg of buffered aspirin, either by chewing a tablet for 30 seconds before swallowing it with 4 ounces of water, swallowing a whole tablet with 4 ounces of water, or drinking 4 ounces of Alka Seltzer. Frequent blood samples were obtained for serum aspirin, salicylate, and thromboxane B2 (TxB2) concentrations. With all formulations of aspirin, serum TxB2 decreased 50% when the plasma aspirin concentration reached approximately 1,000 ng/ml. A 50% and 90% decrease in serum TxB2 occurred more quickly after chewing a tablet than after a tablet was swallowed whole. For example, the t 50% for serum TxB2 inhibition was 5.0 +/- 0.6 minutes with the chewed tablet versus 12.0 +/- 2.3 minutes when the tablet was swallowed (p = 0.01). A 50% decrease in serum TxB2 occurred 7.6 +/- 1.2 minutes after Alka Seltzer solution (p = 0.04 vs chewing a tablet; p = 0.13 vs swallowing a whole tablet). Chewing an aspirin tablet is the most effective way of accelerating absorption of aspirin into the blood and shortening the time required for an antiplatelet effect.

Absorption↗
PubMed1999

cDNA cloning of FRIL, a lectin from Dolichos lablab, that preserves hematopoietic progenitors in suspension culture.

Ex vivo culture of hematopoietic stem cells is limited by the inability of cytokines to maintain primitive cells without inducing proliferation, differentiation, and subsequent loss of repopulating capacity. We identified recently in extracts of kidney bean and hyacinth bean a mannose-binding lectin, called FRIL, and provide here evidence that this protein appears to satisfy properties of a stem cell preservation factor. FRIL was first identified based on its ability to stimulate NIH 3T3 cells transfected with Flt3, a tyrosine kinase receptor central to regulation of stem cells. Molecular characterization from polypeptide sequencing and identification of the cDNA of hyacinth bean FRIL shows 78% amino acid identity with a mannose-binding lectin of hyacinth beans. Treatment of primitive hematopoietic progenitors in suspension culture with purified hyacinth FRIL alone is able to preserve cells for 1 month without medium changes. In vitro progenitor assays for human hematopoietic cells cultured 3 weeks in FRIL displayed small blast-like colonies that were capable of serial replating and persisted even in the presence of cytokines known to induce differentiation. These results suggest that FRIL is capable of preserving primitive progenitors in suspension culture for prolonged periods. FRIL's clinical utility involving procedures for stem cell transplantation, tumor cell purging before autologous transplantation, and ex vivo cultures used for expansion and stem cell gene therapy currently are being explored.

Amino Acid Sequence↗
PubMed1999

MHC class I-restricted epitope spreading in the context of tumor rejection following vaccination with a single immunodominant CTL epitope.

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become targets of an evolving immune response. This phenomenon has been associated most notably with the progression of naturally occurring or experimentally induced chronic autoimmune diseases. We have investigated the potential occurrence of epitope spreading in the context of antitumor cytotoxic T cell (CTL) responses using chicken ovalbumin (OVA) as a model antigen. Our results indicate that following rejection of OVA-expressing EG.7 tumor cells effectuated by a CTL response which is induced against the MHC class I-restricted immunodominant epitope OVA257-264, there occurs intramolecular diversification of the CTL response to two additional OVA-derived epitopes, OVA176-183 and OVA55-62, as well as intermolecular spreading to other endogenous tumor-derived determinants. It seems that CTL-mediated tumor cell destruction in vivo favors cross-presentation of additional epitopes with the consequent activation of additional tumor-reactive lymphocytes. The process of epitope spreading in that context has obvious important implications for the design of antigen-specific antitumor immunotherapies.

Animals↗
PubMed1999

Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.

BACKGROUND & AIMS: The safety of low-dose daily aspirin therapy in the gastrointestinal tract is uncertain. Our objectives were to evaluate the long-term effects of very low daily aspirin doses in the gastrointestinal tract and effects on platelet-derived serum thromboxane levels in volunteers. METHODS: Subjects were randomized to receive 10 mg (n = 8), 81 mg (n = 11), or 325 mg (n = 10) aspirin daily for 3 months. Before administration of aspirin, all subjects underwent gastroduodenoscopy, and most underwent proctoscopy for assessment of mucosal injury and prostaglandin content. After 1.5 and 3 months, subjects again underwent gastroduodenoscopy and, at 3 months, another proctoscopy. RESULTS: Each aspirin dose (even 10 mg) significantly reduced gastric mucosal prostaglandin levels, to approximately 40% of the baseline value. All three doses also induced significant gastric injury, and 325 mg caused duodenal injury. Three subjects developed gastric ulcers, 1 while taking 10 mg/day of aspirin. Furthermore, aspirin at 81 mg/day and 325 mg/day (but not 10 mg/day) significantly reduced duodenal mucosal prostaglandin levels to approximately 40% of the baseline value. Only 325 mg of aspirin per day significantly reduced rectal mucosal prostaglandin levels to approximately 60% of the baseline value. Serum thromboxane levels were inhibited 62%, 90%, and 98% with 10, 81, and 325 mg of aspirin. CONCLUSIONS: The findings explain aspirin's predominant gastric toxicity and question the safety of even 10 mg of aspirin daily.

Adult↗
PubMed1999

The effects of aerosolized dextran in a mouse model of Pseudomonas aeruginosa pulmonary infection.

Airway infections initiated by the interaction of bacterial adhesins with carbohydrate receptors can be potentially prevented by nontoxic carbohydrate inhibitors. Intranasal inoculation of neonatal mice with Pseudomonas aeruginosa PAO1 caused pneumonia in 55% of control mice but in only 13% of mice inoculated 2 h after dextran inhalation (P<.001) and in 28% inoculated 4 h after dextran inhalation (P=.02). PAO1 adherence to epithelial cells was inhibited by 50% in the presence of dextran. Dextran was well distributed throughout the airways and stimulated tumor necrosis factor-alpha production in murine lungs but not interleukin-8 production by human epithelial cell lines. Phagocytosis of PAO1 was not affected by dextran nor was killing by human neutrophils diminished. Administration of dextran by aerosol may prevent murine pneumonia by impeding bacterial access to epithelial receptors and by stimulation of the immune functions of the epithelium.

Aerosols↗
PubMed1999

Induction of antitumor immunity with modified autologous cells expressing membrane-bound murine cytokines.

Development of cytokine gene-modified autologous tumor vaccines must take into account the strictly paracrine physiology of cytokines whose expression at the tumor microenvironment is important for the successful induction of tumor-specific immunity. In this study, we investigated the efficacy of a tumor vaccine composed of inactivated autologous cells transfected with two plasmid vectors encoding a mutant membrane-bound murine granulocyte-macrophage colony-stimulating factor (MuGM-CSF) and murine interferon-gamma (MuIFN-gamma). Expression of both cytokines as cell surface ligands on the highly metastatic D122 clone of Lewis lung carcinoma led to abrogation of their tumorigenicity and metastatic phenotype. More importantly, vaccination with irradiated tumor cells expressing the membrane-bound GM-CSF and IFN-gamma induced a cytotoxic T lymphocyte (CTL) response that protected syngeneic mice against a subsequent challenge with D122 cells as a primary tumor in preimmunized mice as well as against lung metastasis developing after surgical removal of the primary tumor in naive mice. Autologous cells expressing the membrane-bound GM-CSF and IFN-gamma exhibited comparable efficacy as an antimetastatic vaccine to a vaccine composed of transfectants expressing wild-type secreted cytokine molecules. These results indicate that membrane-bound cytokines can cause enhanced immunogenicity when transfected into tumor cells for the induction of antitumor immunity.

Animals↗
PubMed1999

Influence of H. pylori infection on meal-stimulated gastric acid secretion and gastroesophageal acid reflux.

Gastric acid secretion, gastrin release, gastric emptying, and gastroesophageal acid reflux were measured in asymptomatic individuals before and after elimination of Helicobacter pylori gastritis. After basal gastric acid secretion and serum gastrin concentrations were measured, meal-stimulated gastric acid secretion and gastrin release were assessed during in vivo intragastric titration to pH 3. Experiments were repeated 4 wk after treatment with lansoprazole, amoxicillin, and clarithromycin. Esophageal pH was also monitored for 24 h before and after therapy. Basal gastric acidity increased approximately 20 mmol/l in subjects whose infection was eradicated (P < 0.05) but not in those with persistent infection. Basal and meal-stimulated gastric acid secretion did not change after H. pylori eradication, despite a 41% reduction in meal-stimulated gastrin release (P < 0.05). Gastroesophageal acid reflux increased two- to threefold after successful treatment (P < 0. 05) but did not change in subjects with persistent infection. Thus elimination of H. pylori gastritis increases gastric acidity, probably by reducing nonparietal alkaline secretion, and this may facilitate gastroesophageal acid reflux.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

The effect of GH on estrogen receptor expression in the rat mammary gland.

Both GH and insulin-like growth factor I (IGF-I) synergize with estrogen to induce normal mammary gland development. However, the nature of this synergy has not been explored. To gain insight into the mechanism of these interactions we have examined the effects of these substances on the estrogen receptor (ER). ER levels in the mammary gland cytosols from hypophysectomized and oophorectomized rats, were measured using two assay systems: a dextran-coated charcoal procedure to measure binding to radiolabeled steroid, and an immunologic assay employing a specific antibody to the receptor. In both assays, levels of ER were at or near baseline detection (approximately 1-2 ng/mg protein). Treating animals with either bovine or human GH significantly increased ER activity (P<0.001), whereas prolactin (PRL) and/or estradiol treatment had no effect. That this increase was at the level of transcription was demonstrated by reverse transcriptase/polymerase chain reaction. Following a single injection of GH (50 microgram), a substantial increase in ER mRNA was observed by 10 h, with levels returning to baseline within 24 h; a concomitant increase in ER itself was also observed at the 10 h time point. The effect of GH appeared to occur mainly in the mammary stroma, because there were no differences in GH stimulation of ER between gland-free and gland containing mammary fat pads. Furthermore, analysis of mammary gland ER by immunocytochemistry demonstrated that while ER was present in the epithelial cells of non-treated animals, only GH treated animals had ER clearly visible in both glandular and fat cells of the tissue. In contrast, treating animals with des(1-3)-IGF-I did not result in reproducible increases in ER, nor in the staining of fat cell nuclei for ER. These data demonstrate a specific GH effect on the ER in the mammary fat cell.

Animals↗
PubMed1998

Interferon alpha and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS.

HIV type 1 (HIV-1) not only directly kills infected CD4(+) T cells but also induces immunosuppression of uninfected T cells. Two immunosuppressive proteins, interferon alpha (IFNalpha) and extracellular Tat, mediate this process because specific antibodies against these proteins prevent generation of suppressor cells in HIV-1-infected peripheral blood mononuclear cell cultures. Furthermore, the production of C-C chemokines in response to immune cell activation, initially enhanced by IFNalpha and Tat, ultimately is inhibited by these proteins in parallel with their induction of immunosuppression. The clinical corollary is the immunosuppression of uninfected T cells and the decline in C-C chemokine release found at advanced stages of HIV-1 infection paralleling rising levels of IFNalpha and extracellular Tat. We, therefore, suggest that IFNalpha and Tat may be critical targets for anti-AIDS strategies.

Acquired Immunodeficiency Syndrome↗
PubMed1998

C-C chemokines, pivotal in protection against HIV type 1 infection.

Exposure to HIV type 1 (HIV-1) does not usually lead to infection. Although this could be because of insufficient virus titer, there is now abundant evidence that some individuals resist infection even when directly exposed to a high titer of HIV. This protection recently has been correlated with homozygous mutations of an HIV-1 coreceptor, namely CCR5, the receptor for the beta-chemokines. Moreover, earlier results already had shown that the same chemokines markedly suppress the nonsyncitial inducing variants of HIV-1, the chief virus type transmitted from person to person. CCR5 mutation, as a unique mechanism of protection, is, however, suspect because HIV-1 variants can use other chemokine receptors as their coreceptor. Moreover, recent results have established that infection can indeed sometimes occur with such mutations. Here, we report on transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated Factor VIII concentrate from plasma during 1980-1985 before the development of the HIV blood test. Furthermore, and remarkably, 14 subjects remain uninfected to this date, and in these subjects we found homozygous CCR5 mutations in none but in most of them overproduction of beta chemokines. In vitro experiments confirmed the potent anti-HIV suppressive effect of these chemokines.

Cells, Cultured↗
PubMed1998

Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.

PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 microM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P < 0.001) and with COX-1 selectivity (P < 0.01), but not with COX-2 inhibitory potency. Even COX-2 "selective" NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

Adult↗