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Biomedical subjects

J A Gonzalo

Publications and source records attributed to J A Gonzalo.

At least 19 recordsLinked to original sources
PubMed2005

The Bispectral Index Scale: its use in the detection of brain death.

OBJECTIVE: To evaluate the Bispectral Index Scale (BIS) monitor as a method of brain death (BD) detection. PATIENTS AND METHODS: We performed an observational prospective study in an intensive care unit (ICU) of a university hospital of 19 patients hospitalized nonconsecutively in the ICU with serious neurologic pathology and evolution toward BD. A BIS monitor, XP model, and the sensor "BIS Quatro" were used to continuously record values: suppression ratio (SR), quality of the signal index, and electromyographic (EMG) activity. RESULTS: The BD diagnosis was made through neurological clinical exploration and electroencephalogram (EEG) in all the cases. Additionally, transcranial Doppler was used in 13 patients. Coincident with clinical worsening, it was observed that there was a gradual decrease of the BIS value, together with a rise in the SR. In all the patients in which the BD diagnosis was confirmed, the BIS showed values of 0 and suppression rates of 100. Only one patient showed interferences, due to EMG activity, the same problem was detected when a conventional EEG was performing. After using a neuromuscular blocker, the values of BIS and SR were 0 and 100, respectively. CONCLUSIONS: The BIS is a noninvasive, simple, and easy to interpret method. All the patients with BD diagnosis except for one had a BIS value of 0 and TS of 100, showing a perfect correlation with the other diagnostic methods. The BIS cannot be used on its own for the confirmation of the BD, but it is a useful tool to detect the beginning of brain herniation.

Brain Death↗
PubMed2001

Dynamic scaling in diluted systems: deactivation through thermal dilution.

Activated scaling is confirmed to hold in transverse field-induced phase transitions of randomly diluted Ising systems. Quantum Monte Carlo calculations have been made not just at the percolation threshold (pc) but also well below and above it. We follow the evolution of the activated scaling at zero temperature in the phase transition from ferromagnetic to quantum Griffiths phase (p>pc) at the phase boundary (p=pc) and for transitions inside the nonferromagnetic quantum Griffiths phase (p<pc). A novel deactivation phenomenon inside the nonferromagnetic Griffiths-McCoy phase (p<pc) is observed using a thermal (in contrast to random) dilution of the system.

Journal Article↗
PubMed2001

Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-3 and tissue leukocyte apoptosis.

We have used two models of murine pulmonary inflammation to investigate the signals responsible for the resolution of bronchial hyperresponsiveness (BHR). Both protocols involved two sensitizations with OVA followed by serial aerosolized challenge with OVA. We determined that administration of the second sensitization by aerosol (model A) was associated with a transient response, whereas administration by the i.p. route (model B) induced a sustained response, in the form of BHR and eosinophilia. This difference in kinetics was due solely to the route of the second Ag administration and was not associated with Ag dose or adjuvant. Differences in kinetics of lung eosinophilia/BHR were shown to be independent of IgE levels and IL-4 or IL-5. However, IL-3 levels in model A closely correlated with the rate of leukocyte clearance by apoptosis and were observed concomitant with a decline in BHR. Blockage of IL-3 in model B increased leukocyte apoptosis but reduced tissue eosinophilia and BHR. The use of mouse models in which a single different administration of allergen is associated with a failure/success to resolve inflammation and BHR by 72 h postchallenge indicates a link between IL-3 production, leukocyte apoptosis, and BHR responses.

Animals↗
PubMed2001

Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation.

Optimal T cell activation requires engagement of CD28 with its counterligands B7-1 and B7-2. Inducible costimulator (ICOS) is the third member of the CD28/CTLA4 family that binds a B7-like protein, B7RP-1. Administration of ICOS-Ig attenuates T cell expansion following superantigen (SAg) administration, but fails to regulate either peripheral deletion or anergy induction. ICOS-Ig, but not CTLA4-Ig, uniquely regulates SAg-induced TNF-alpha production, whereas IL-2 secretion is modulated by CTLA4-Ig, but not ICOS-Ig. In contrast, both ICOS and CD28 are required for complete attenuation of IL-4 production. Our data suggest that ICOS and CD28 regulate T cell expansion and that ligation of either CD28 or ICOS can either uniquely regulate cytokine production (IL-2/TNF-alpha) or synergize for optimal cytokine production (IL-4) after SAg administration.

Abatacept↗
PubMed2001

ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses.

We examined the requirement for and cooperation between CD28 and inducible costimulator (ICOS) in effective T helper (TH) cell responses in vivo. We found that both CD28 and ICOS were critical in determining the outcome of an immune response; cytolytic T lymphocyte-associated antigen 4-immunoglobulin (CTLA-4-Ig), ICOS-Ig and/or a neutralizing ICOS monoclonal antibody attenuated T cell expansion, TH2 cytokine production and eosinophilic inflammation. CD28-dependent signaling was essential during priming, whereas ICOS-B7RP-1 regulated TH effector responses, and the up-regulation of chemokine receptors that determine T cell migration. Our data suggests a scenario whereby both molecules regulate the outcome of the immune response but play separate key roles: CD28 primes T cells and ICOS regulates effector responses.

Abatacept↗
PubMed2000

Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease.

Stromal cell-derived factor-1alpha/beta (SDF-1alpha/beta) is phylogenetically a primitive chemokine widely expressed in a variety of tissues and cell types. This expression is detectable in the absence of stimuli provided by bacterial or viral infections and allergic or autoimmune disorders. Based on these and other findings, SDF-1alpha has not been considered an inflammatory chemokine, but, rather, has been believed to be involved in certain homeostatic processes, such as leukocyte recirculation. SDF-1alpha is a potent chemoattractant for lymphocytes and monocytes that mediates its activity via the chemokine receptor CXCR4. Study of the role of SDF-1alpha/CXCR4 in vivo during inflammation has been limited by the fact that transgenic mice that have been made deficient in either molecule die early in life due to developmental defects. The present study was aimed at evaluating the functional relevance of the SDF-1alpha/CXCR4 axis during an inflammatory process. Neutralizing Abs to CXCR4 reduced lung eosinophilia (bronchoalveolar lavage fluid and interstitium) by half, indicating that CXCR4-mediated signals contribute to lung inflammation in a mouse model of allergic airway disease (AAD). This reduction in inflammation was accompanied by a significant decrease in airway hyper-responsiveness. SDF-1alpha neutralization resulted in similar reduction in both lung allergic inflammation and airway hyper-responsiveness. Retroviral delivery of a CXCR4 cDNA to leukocytes resulted in greater inflammation when transduced mice were subjected to a mouse model of AAD. These results highlight that, although considered a noninflammatory axis, the involvement of CXCR4 and SDF-1alpha is critical during AAD, and this receptor and its ligand are potentially relevant in other inflammatory processes.

Administration, Intranasal↗
PubMed2000

The CD28-related molecule ICOS is required for effective T cell-dependent immune responses.

While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and IFNgamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses.

Abatacept↗
PubMed2000

Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung.

The understanding of the relative contribution of particular chemokines to the selective accumulation of leukocyte subsets to an organ site during an inflammatory response is made difficult by the simultaneous presence of multiple chemokines with partially overlapping functions at the inflammatory site. The study of several chemokine pathways (expression and function) during the development of a mouse model of allergic airway disease (AAD) has revealed differential expression regulation with distinct cellular sources for individual chemokines with functional bias for the recruitment/localization of regulatory and/or effector leukocyte subsets. In the present review, we propose that distinct functional groups of chemokines co-operate to generate the complete inflammatory response in the lung during AAD. We will also extend these concepts to the specific recruitment of a key cellular subset such as T helper type 2 (Th2) lymphocytes. We propose that the long term recruitment of antigen-specific Th2 cells to target organs, such as airways during chronic lung inflammation, is the result the sequential involvement of several chemotactic axes. Specifically, the CCR3/eotaxin and the CCR4/MDC pathway act in a coordinated co-operative manner, with the CCR3/eotaxin pathway being critical in the acute/early stages of a response, followed by the CCR4/MDC pathway, which ultimately dominates in the recruitment of antigen-specific Th2 cells. Other chemokines/receptors participate in this process possibly by amplifying/priming the Th2 recruitment response.

Animals↗
PubMed1999

Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation.

The cloning, expression, and function of the murine (m) homologue of human (h) monocyte-derived chemokine (MDC) is reported here. Like hMDC, mMDC is able to elicit the chemotactic migration in vitro of activated lymphocytes and monocytes. Among activated lymphocytes, Th2 cells were induced to migrate most efficiently. mMDC mRNA and protein expression is modulated during the course of an allergic reaction in the lung. Neutralization of mMDC with specific Abs in a model of lung inflammation resulted in prevention of airway hyperreactivity and significant reduction of eosinophils in the lung interstitium but not in the airway lumen. These data suggest that mMDC is essential in the transit/retention of leukocytes in the lung tissue rather than in their extravasation from the blood vessel or during their transepithelial migration into the airways. These results also highlight the relevance of factors, such as mMDC, that regulate the migration and accumulation of leukocytes within the tissue during the development of the key physiological endpoint of asthma, airway hyperreactivity.

Amino Acid Sequence↗
PubMed1999

Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness.

ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an essential role for ICAM-2 in the development of the inflammatory and respiratory components of allergic lung disease. This phenotype is caused by the lack of ICAM-2 expression on non-hematopoietic cells. ICAM-2 deficiency on endothelial cells causes reduced eosinophil transmigration in vitro. ICAM-2 is not essential for lymphocyte homing or the development of leukocytes, with the exception of megakaryocyte progenitors, which are significantly reduced.

Administration, Inhalation↗
PubMed1999

Selective eosinophil transendothelial migration triggered by eotaxin via modulation of Mac-1/ICAM-1 and VLA-4/VCAM-1 interactions.

We have recently cloned eotaxin, a highly efficacious eosinophilic chemokine involved in the development of lung eosinophilia during allergic inflammatory reactions. To understand more precisely how eotaxin facilitates the specific migration of eosinophils, we have studied which adhesion receptors are essential for eotaxin action both in vivo and in vitro. Experiments using mice genetically deficient in adhesion receptors demonstrated that molecules previously reported to be involved in both leukocyte tethering/rolling (P-selectin and E-selectin) and in sticking/ transmigration (ICAM-1 and VCAM-1) are required for eotaxin action in vivo. To further elucidate the mechanism(s) involved in this process, we have used an in vitro transendothelial chemotaxis model. mAb neutralization studies performed in this system suggest that the integrins Mac-1 (CD11b/18), VLA-4 (alpha4beta1) and LFA-1 (CD11a/18) are involved in the transendothelial chemotaxis of eosinophils to eotaxin. Accordingly, the expression of these integrins on eosinophils is elevated by direct action of this chemokine in a concentration-dependent manner. Taken together, our results suggest that eotaxin-induced eosinophil transendothelial migration in vivo and in vitro relies on Mac-1/ICAM-1 and VLA-4NCAM-1 interactions, the latter ones becoming more relevant at later time points of the eotaxin-induced recruitment process.

Animals↗
PubMed1999

Self-averaging of random and thermally disordered diluted Ising systems.

Self-averaging of singular thermodynamic quantities at criticality for randomly and thermally diluted three-dimensional Ising systems has been studied by the Monte Carlo approach. Substantially improved self-averaging is obtained for critically clustered (critically thermally diluted) vacancy distributions in comparison with the observed self-averaging for purely random diluted distributions. Critically thermal dilution, leading to maximum relative self-averaging, corresponds to the case when the characteristic vacancy ordering temperature (theta) is made equal to the magnetic critical temperature for the pure three-dimensional (3D) Ising systems (T(3D)(c)). For the case of a high ordering temperature (theta>>T(3D)(c)), the self-averaging obtained is comparable to that in a randomly diluted system.

Journal Article↗
PubMed1998

The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness.

The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1alpha, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes.

Animals↗
PubMed1998

The chemotactic cytokine eotaxin acts as a granulocyte-macrophage colony-stimulating factor during lung inflammation.

During inflammatory processes, inflamed tissues signal the bone marrow (BM) to produce more mature leukocytes in ways that are not yet understood. We report here that, during the development of lung allergic inflammation, the administration of neutralizing antibodies to the chemotactic cytokine, Eotaxin, prevented the increase in the number of myeloid progenitors produced in the BM, therefore reducing the output of mature myeloid cells from BM. Conversely, the in vivo administration of Eotaxin increased the number of myeloid progenitors present in the BM. Furthermore, we found that, in vitro, Eotaxin is a colony-stimulating factor for granulocytes and macrophages. Eotaxin activity synergized with stem cell factor but not with interleukin-3 or granulocyte-macrophage colony-stimulating factor and was inhibited by pertussis toxin. We report also that CCR-3, the receptor for Eotaxin, was expressed by hematopoietic progenitors (HP). Thus, during inflammation, Eotaxin acts in a paracrine way to shift the differentiation of BM HP towards the myeloid lineage.

Animals↗
PubMed1997

Intercellular adhesion molecule-1 deficiency prolongs survival and protects against the development of pulmonary inflammation during murine lupus.

One of the characteristic features of the lupus syndrome in humans and mice is the organ-specific accumulation of leukocytes within a variety of different tissues; however, the etiology of this phenomenon remains unclear. The work presented here determined the role of intercellular adhesion molecule (ICAM)-1 in the development of pulmonary leukocyte accumulation by generating MRL/MpJ-Faslpr mice that are genetically deficient in this critical adhesion molecule. Interestingly, these MRL/MpJ-Faslpr ICAM-1 knockout mice exhibit prolonged survival times compared to littermates expressing ICAM-1. We have determined that lack of ICAM-1 completely abrogates the development of pulmonary inflammation but does not prevent the development of autoantibodies, lymphadenopathy, and glomerulonephritis. Furthermore, the lack of pulmonary inflammation was found to be due to decreased migration of leukocytes to the lung rather than decreased in situ proliferation of cells.

Animals↗
PubMed1997

Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation.

Chemokines are small secreted proteins that stimulate the directional migration of leukocytes and mediate inflammation. During screening of a murine choroid plexus complementary DNA library, we identified a new chemokine, designated neurotactin. Unlike other chemokines, neurotactin has a unique cysteine pattern, Cys-X-X-X-Cys, and is predicted to be a type 1 membrane protein. Full-length recombinant neurotactin is localized on the surface of transfected 293 cells. Recombinant neurotactin containing the chemokine domain is chemotactic for neutrophils both in vitro and in vivo. Neurotactin messenger RNA is predominantly expressed in normal murine brain and its protein expression in activated brain microglia is upregulated in mice with experimental autoimmune encephalomyelitis, as well as in mice treated with lipopolysaccharide. Distinct from all other chemokine genes, the neurotactin gene is localized to human chromosome 16q. Consequently we propose that neurotactin represents a new delta-chemokine family and that it may play a role in brain inflammation processes.

Animals↗