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Biomedical subjects

G Nunez

Publications and source records attributed to G Nunez.

At least 37 records · Page 2Linked to original sources
PubMed1995

Diazepam induces tolerance in the isolated skin of Pleurodema thaul.

The effects of the long-term administration of diazepam on the potential difference and short-circuit current of the isolated skin of the toad Pleurodema thaul (P. thaul) were investigated. Diazepam applied in a concentration range of 4.6 x 10(-6) to 5.2 x 10(-5) M decreased both electrical parameters. This response was unaffected by flumazenil indicating that the action of diazepam is not induced through benzodiazepine receptors. Induction of tolerance to diazepam on its observed effects on potential difference and short-circuit current was obtained by the administration of a single dose of the drug in a slow release preparation. Skins tolerant to diazepam were also tolerant to the acute effects of verapamil on both electric parameters. Tolerance to diazepam effects was partly reversed by increasing Ca2+ concentration in the inner bathing solution. The results are consistent with a Ca2+ channel blocking effect of diazepam in the P. thaul skin.

Animals↗
PubMed1995

Diazepam decreases the response to the electrical stimulation of the nerve-skin preparation of the toad Caudiverbera caudiverbera.

1. The effect of diazepam was examined in the nerve skin preparation of the toad Caudiverbera caudiverbera. 2. Nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD), which consisted of a rapid and then a slow component. 3. Diazepam concentrations from 5.0 x 10(-5)M to 5.1 x 10(-4)M caused a dose-dependent block of both components to a 30% of their control values and also reduced the stimulatory responses to noradrenaline in this preparation. 4. Diazepam antagonized the potassium blocking effect of barium. 5. These results, based on electrophysiological and pharmacological evidence, are consistent with a calcium and sodium blocking effect of diazepam on the nerve skin junction of C. caudiverbera.

Adrenergic alpha-Agonists↗
PubMed1995

Age-dependent injury in human umbilical vein endothelial cells: relationship to apoptosis and correlation with a lack of A20 expression.

BACKGROUND: It has recently been shown that human umbilical vein endothelial cells (HUVEC) become increasingly sensitive to growth factor deprivation, resulting in cell death, as a function of age in culture. The overall goal of the present study was to investigate the mechanism of lethal injury in these cells and compare the injury process to other known mechanisms of injury in the same cells. EXPERIMENTAL DESIGN: HUVEC were established in culture and maintained for four passages. Injury to first-passage cells and fourth-passage cells were examined for injury in the presence of agents that are known to confer resistance to apoptosis. Ultrastructural features of injury and DNA fragmentation patterns were assessed. Expression of factors that are known to be associated with resistance to apoptosis in other models were assessed. RESULTS: Fourth-passage HUVEC undergoing injury exhibited morphologic features characteristic of apoptosis and DNA fragmentation. Agents known to inhibit apoptotic cell injury in other models inhibited injury. A20 expression was correlated with resistance to injury in fourth-passage HUVEC, but there was no correlation between bcl-2 and bcl-x expression and resistance to injury. CONCLUSIONS: HUVEC injury resulting from growth factor deprivation increases as a function of age in vitro and appears to be a form of apoptosis. A20 expression may confer resistance to cell injury through this pathway.

Apoptosis↗
PubMed1993

Programmed cell death by bcl-2-dependent and independent mechanisms in B lymphoma cells.

Programmed cell death (PCD) or apoptosis is a common form of cellular demise during embryogenesis, tumorigenesis and clonal selection in the immune system. The bcl-2 proto-oncogene has been recently implicated as a potential physiological regulator of the PCD pathway. Gene transfer studies have shown that overexpression of bcl-2 blocks apoptosis mediated by several stimuli in cultured cell lines and promotes the survival of B and T lymphocytes in transgenic mice. However, it remains unclear whether under normal conditions bcl-2 is responsible for controlling cell death. We have investigated the role of bcl-2 in the antimembrane IgM (mIgM)-induced apoptotic death of WEHI-231 B cell lymphoma, a model that mimics clonal deletion of immature B cells by antigen. Signalling of mIgM receptors triggered downregulation of both bcl-2 RNA and protein, and induced apoptosis in WEHI-231 B cells. This effect appeared to be specific since (i) the levels of beta 2-microglobulin and beta-actin RNA remain unchanged and (ii) signalling of the apoptosis-resistant B cell lymphoma line BAL-17 with anti-mu was not associated with downregulation of bcl-2 RNA. However, stable expression of bcl-2 by transfection did not rescue WEHI-231 B cells from apoptosis, yet WEHI-231 cells overexpressing bcl-2 were more resistant to programmed cell death induced by heat-shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis↗
PubMed1993

Effects of local geometry and fluid dynamics on regional platelet deposition on artificial surfaces.

An important aspect of blood-material interactions is the activation, adhesion, and subsequent aggregation of blood platelets on the artificial surface, all of which are directly affected by local fluid dynamics. The objective of this work was to directly correlate changing local fluid dynamic conditions produced by various vessel geometries, including stenosis, aneurysm, and separate contraction and expansion geometries, with quantitative in vitro measurements of regional platelet deposition. We directly measured platelet deposition as a function of axial position along four Lexan flow chambers with axisymmetric models of these geometries using 111In-labeled platelets. Platelet deposition was maximum in observed areas of flow recirculation and reattachment and minimum in locations of high shear and separation. For the stenosis geometry, two distinct regions of increased platelet deposition were apparent, one proximal to and one distal to the stenosis throat. An approximately linear increase in platelet densities was produced in the aneurysm region, increasing in the direction of flow. Through a comparison of platelet deposition with local fluid streamline orientation, we have shown that platelet deposition is increased in certain areas due to the enhanced convective transport of platelets and blood cells to the vessel wall along locally curved streamlines with velocity components perpendicular to the vessel wall.

Aneurysm↗
PubMed1991

A mathematical description of pressures in alveolar pores of Kohn.

Small interalveolar holes within the lung are called pores of Kohn. Some researchers have correlated enlarged pore size with diseases, e.g. emphysema, that are characterized by tissue destruction. Mathematical models of the pressures generated in closed, fluid-filled and open, fluid-lined pores demonstrate that pressures capable of rupturing lung tissue can be developed in a pore due to the surface tension and shape of the air-liquid interface. Pore enlargement accompanied by tissue destruction is presented as a possible mechanism for the disease process observed during aging and the development of emphysema in the lung.

Humans↗
PubMed1990

Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population.

We characterized the basis for the follicular lymphoproliferation in transgenic mice bearing a Bcl-2-immunoglobulin (Bcl-2-Ig) minigene representing the t(14;18) of human follicular lymphoma. Discriminatory S1 nuclease protection assays revealed that the Bcl-2-Ig transgene was overexpressed relative to endogenous mouse Bcl-2 in spleen and thymus. Western (immunoblot) analysis demonstrated the overproduction of the human 25-kilodalton Bcl-2 protein, which arose from the transgene, in spleen, thymus, and the expanded B-cell subset. Despite the generalized lymphoid pattern of deregulation, two-color flow cytometry and density gradient centrifugation indicated that the expanded lymphocytes were predominantly small, resting B cells coexpressing B220, immunoglobulin M (IgM), IgD, Ia, and kappa. Cell cycle analysis confirmed that about 97% of these expanded B cells reside in G0/G1. An extensive characterization of transgenic lines revealed a fourfold excess of IgM-IgD-expressing B cells in spleen and dramatically increased numbers in bone marrow. While resting, these cells proliferated in response to lipopolysaccharide and anti-IgM and demonstrated normal B-cell colony formation in soft agar. Moreover, these B cells, which demonstrated an extended survival in vitro even in the absence of stroma, were also resting in G0, yet were capable of proliferative responses. These findings provide consistent evidence that the accumulation of B cells after Bcl-2 overproduction is secondary to prolonged cell survival and not increased cell cycling. This suggests a unique role for Bcl-2 as a proto-oncogene that enhances cell survival independent of promoting cell division.

Animals↗
PubMed1989

bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation.

Human follicular B cell lymphomas possess a t(14;18) interchromosomal translocation that juxtaposes the putative proto-oncogene bcl-2 with the immunoglobulin (Ig) heavy chain locus. We generated minigene constructs representing the bcl-2-Ig fusion gene found at this chromosomal breakpoint. These constructs were placed into the germ line of mice to assess the effects of the t(14;18) during development. The transgene demonstrates a lymphoid pattern of expression and uniformly results in an expanded follicular center cell population. Hyperplastic splenic follicles coalesce to form massive regions of splenic white pulp. Mice over 15 weeks of age demonstrate regional lymphadenopathy with abnormal cellular infiltrates. The expanded lymphoid compartment is composed predominantly of polyclonal B220-positive, IgM/IgD-positive B cells. Provocatively, the bcl-2-Ig transgene confers a survival advantage to a population of mature B cells assessed in vitro. bcl-2-Ig transgenic mice document a prospective role for the t(14;18) in B cell growth and the pathogenesis of follicular lymphoma.

Animals↗
PubMed1989

Growth- and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells.

Human follicular B-cell lymphomas possess a t(14;18) that translocates a putative protooncogene, BCL2, into the immunoglobulin heavy chain locus. The normal BCL2 gene is quiescent in resting B cells, expressed in proliferating, but down-regulated in differentiated B cells. Inappropriately high levels of BCL2-immunoglobulin chimeric RNA are present in t(14;18) lymphomas for their mature B-cell stage. We examined the biologic effects of BCL2 deregulation in human B cells by introducing BCL2 into human B-lymphoblastoid cell lines (LCLs) with retroviral gene transfer. Although deregulated BCL2 expression as a single agent was not sufficient to confer tumorigenicity to LCLs, it consistently produced a 3- to 4-fold increment in LCL clonogenicity in soft agar. In addition, BCL2 deregulation complements the transforming effects of the MYC oncogene in LCLs. BCL2 augmented the clonogenicity of LCLs bearing exogenous MYC and increased the frequency and shortened the latency of tumor induction in immunodeficient mice. These results demonstrate a role for BCL2 as a protooncogene that affects B-cell growth and enhances B-cell neoplasia.

Animals↗
PubMed1988

Human delta T cell receptor: rearrangement, deletion, and translocation.

Individual T cells express the CD3 molecule in association with alternative gamma delta or alpha beta heterodimeric T cell receptors (TCR). The delta TCR, used in one type of T cell is located within the alpha TCR gene used in quite another cell. T cell precursors and occasional gamma delta T cells in humans possess an unexpected 2.0 Kb mRNA in which a tandemly repeated motif, T early alpha (TEA), has been spliced to the constant (C alpha) region. Long range pulse field gel mapping as well as molecular cloning reveal that TEA is located immediately 5' to the most upstream joining (J alpha) segments of the alpha TCR locus. The human delta TCR locus is immediately 5' to TEA and diversity (D delta 1 +2), J delta 1 +2, C delta, and TEA are linked within 35 Kb. The human delta TCR locus conserves a 12/23 bp spacer paradigm and D delta 1 and D delta 2 are frequently recombined as D delta 1/D delta 2, and reveal exonucleolytic trimming with extensive "N" segment addition. Thus, despite the predominant use of one V delta and J delta segment considerable delta diversity is generated. T cell acute lymphoblastic leukemias (ALL) represent clonal expansions of maturationally arrested cells at specific stages of thymic ontogeny. The gamma delta T-ALLs display allelic exclusion for the delta TCR. Moreover, pre T cells within this group indicate that delta TCR rearrangement can occur prior to the activation of gamma, beta, and alpha loci.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Deletion↗
PubMed1987

HLA-D region epitopes associated with juvenile arthritis. Recognition by alloreactive T cell clones and alloantisera.

The HLA-D region antigens DR5 (w11,w12), DRw6 (w13,w14), DRw8, DRw52, and DQw1 have previously been shown to be increased in frequency in subsets of patients with juvenile arthritis. Since the HLA-D region is complex (composed of at least 3 subregions encoding multiple molecules, each in turn presenting multiple alloantigenic epitopes), we sought to clarify whether one strongly associated factor might explain the previous findings. To search for the pertinent HLA-D region stimulatory epitopes, alloreactive T cells were primed against DR5 and DRw6 haplotypes and cloned by limiting dilution. Three T cell clones and 1 alloantiserum met the criteria for significant association with juvenile arthritis on patient testing, including DR5, DRw6, and DRw8 haplotypes. Monoclonal antibody blocking revealed that all 4 recognized epitopes on DR subregion products. For 2 of the clones, the relative risks for JA (10.5 and 9.4) were higher than the risks with any other previously described typing reagents.

Antibodies, Monoclonal↗
PubMed1987

Antigen presentation by adherent cells from human peripheral blood. Correlation between T-cell activation and expression of HLA-DQ and -DR antigens.

The ability of cells with different amounts of HLA-DQ or -DR to support T-cell proliferation in response to foreign antigens was investigated. Adherent cells were stained with monoclonal antibodies and sorted in the fluorescence-activated cell sorter (FACS) into (a) DQ-positive and DQ-negative subsets, with monoclonal anti-DQ; or (b) subsets expressing different density of DR determinants. Expression of HLA-DQ correlated with increased density of DR. The subset of cells expressing detectable DQ and increased density of DR was found to be more efficient in presenting mumps or tetanus toxoid antigen to T cells than were the DQ-negative, low-DR density adherent cells. Similar results were obtained with primary cultures of T cells from blood and with cloned antigen-specific T-cell lines, restricted by a single DR-subregion specificity. Our results suggest that quantitative variation in DR/DQ molecules expressed on monocytes correlates with their ability to support T-cell responses to nominal antigens. It is not clear whether this is due to only class II antigen density on the surface of the accessory cells or whether other factors are involved.

Antigen-Presenting Cells↗
PubMed1986

[Not Available].

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Cardiology↗
PubMed1986

Human alveolar macrophages: HLA-DR-positive macrophages that are poor stimulators of a primary mixed leukocyte reaction.

Previous studies demonstrated that alveolar macrophages (AM) from most normal human volunteers failed to stimulate the antigen-induced proliferation of peripheral blood T lymphocytes although greater than 90% of AM expressed HLA-DR antigens. The current studies establish that AM also fail to induce allogeneic peripheral blood mononuclear cells to proliferate in a mixed leukocyte reaction (MLR). Suppressive activity by AM was not an explanation for their failure to induce an MLR. Indirect immunofluorescence established the presence of both HLA-DR and DQ antigens on the majority of AM and the persistence of these antigens on cells in culture for up to 6 days, the period of time required to observe a maximal MLR. Metabolic labeling experiments also demonstrated that HLA-DR antigens were synthesized by AM. It was recently reported that AM secrete relatively small amounts of IL 1, an important ancillary signal provided by accessory cells to enhance the stimulation of lymphocyte proliferation. However, addition of optimal concentrations of IL 1 to cultures containing AM failed to enhance the MLR. Thus, there is at least one additional, but as yet undefined, requirement for an accessory cell to induce an optimal MLR besides the display of HLA-D region antigens and the secretion of IL 1. In contrast, AM were effective in specifically stimulating proliferation of alloreactive T cell lines, suggesting that at least some cell lines do not require this nonspecific undefined second signal. We speculate that although AM may not initiate primary immune responses in the lung, they may be important in maintaining immune-mediated inflammatory responses by specifically restimulating already activated T cells.

Adult↗