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Yoseph A Mekori

Publications and source records attributed to Yoseph A Mekori.

14 recordsLinked to original sources
PubMed2006

CD40 ligand and risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.

BACKGROUND: CD40 ligand (CD40L) is a trimeric, transmembrane protein of the tumor necrosis factor family and together with its receptor CD40 is an important contributor to the inflammatory processes that lead to atherosclerosis, plaque destabilization, and thrombosis. METHODS: In order to assess the association between serum concentrations of CD40 ligand (CD40L) and risk of future ischemic stroke and coronary events among patients with chronic CHD, we obtained baseline serum samples from patients (n = 3090) with chronic CHD enrolled in a secondary prevention trial. With a prospective nested case-control design, we measured baseline CD40L concentration in sera of patients who subsequently developed myocardial infarction, sudden cardiac death or ischemic stroke during follow-up (cases, n = 233) and in 233 age- and gender-matched pairs without any subsequent cardiovascular events. RESULTS: Relative odds for recurrent cardiovascular events per one natural log unit difference of CD40L were 0.97 (95%CI, 0.82-1.16). No increase in relative odds for recurrent cardiovascular events was observed per increasing quartiles of CD40L concentrations. In analysis for individual end-points, different trends of risks were observed beyond the 95 percentile for ischemic stroke (OR 2.22; 95%CI, 0.46-12.5) and for recurrent coronary events (OR 0.35; 95%CI, 0.07-1.37), but falling short of statistical significance. CONCLUSION: High serum concentrations of CD40L were not associated with increased risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.

Biomarkers↗
PubMed2006

Mast cells: not only in allergy.

The past decade has confronted us with a striking abundance of novel findings regarding the roles of mast cells in immune responses in health and disease. Newly developed models and techniques have enabled clear-cut dissection of the mast cell contribution in these settings. We now understand that mast cells possess critical effector functions not only within the traditional context of allergic reactions. It is likely that mast cells played pivotal roles in primitive immune systems, yet these functions have been masked in the recent eras by newer immune functions, such as adaptive immunity. Conceivably, mast cells should be refocused on so as to obtain new insights about diverse pathologic conditions, ultimately leading to novel therapeutic approaches targeting these fascinating cells.

Animals↗
PubMed2006

Mast cell apoptosis.

Apoptosis is a physiological form of cell death. Cells undergoing apoptosis execute a genetically controlled program that leads to organized breakdown of cellular structures and ends in phagocytosis of their remains. In mast cells, several mechanisms regulating apoptosis have been identified including growth factors, tumor necrosis factor-alpha receptors, monomeric IgE, Toll-like receptors, and proteins of the bcl-2 family. Methods used to characterize apoptosis of mast cells are reviewed, with special attention to flow cytometric analysis of annexin V staining, analysis of deoxyribonucleic acid fragmentation by gel electrophoresis and end-labeling techniques, measurement of caspase activity by enzymatic assays, and characterization of pro- and anti-apoptotic proteins by immunoblotting.

Animals↗
PubMed2005

Mast cells, which interact with Escherichia coli, up-regulate genes associated with innate immunity and become less responsive to Fc(epsilon)RI-mediated activation.

Mast cells, which are associated with T helper cell type 2-dependent inflammation, have now been implicated in the innate immune response. To further characterize how mast cells are programmed to respond to infectious organisms, we used expression profiling using DNA microarray analysis of gene expression by human mast cells (huMC) during ingestion of Escherichia coli and examined immunoglobulin E (IgE)-mediated degranulation. Analysis of data revealed that specific groups of genes were modulated, including genes encoding transcription factors, cell signaling molecules, cell cycle regulators, enzymes, cytokines, novel chemokines of the CC family, adhesion molecules, and costimulatory molecules. Enzyme-linked immunosorbent assay analysis confirmed the production of tumor necrosis factor and the chemokines CC chemokine ligand (CCL)-1/I-309, CCL-19/macrophage-inflammatory protein-3beta (MIP-3beta), and CCL-18/MIP-4; flow cytometry confirmed the up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1, the integrin CD49d, and CD80. Coincubation with E. coli down-regulated Fc receptor for IgE I (FcepsilonRI) expression and FcepsilonRI-mediated huMC degranulation. These data are consistent with the concept that bacterial exposure directs mast cell responses toward innate immunity and away from IgE-mediated effects.

Cell Adhesion Molecules↗
PubMed2005

Monocyte chemoattractant protein-1 and recurrent cardiovascular events in patients with stable coronary heart disease.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) participates in the recruitment of mononuclear cells to the vessel wall. HYPOTHESIS: The aim of the study was to evaluate the potential association between serum concentration of MCP-1 and risk of future cardiovascular events in patients with chronic coronary heart disease. METHODS: A nested case control design was used. Baseline serum samples were taken from patients with coronary heart disease who were enrolled in a secondary prevention study. The MCP-1 levels were measured in those patients who had recurrent cardiovascular events during follow-up (n = 233) and compared with levels in age- and gender-matched controls. RESULTS: There were no differences in serum MCP-1 levels between cases and controls. The relative odds of a recurrent cardiovascular event for each 1 standard deviation difference in MCP-1 serum concentration (160 pg/ml) was 1.19 (95% confidence interval, 0.95-1.45). No increase in the relative odds for recurrent cardiovascular events was observed per increasing tertiles of MCP-1 concentrations. CONCLUSION: Elevated MCP-1 levels are not associated with long-term risk of cardiovascular events in patients with stable coronary disease.

Aged↗
PubMed2005

Mast cells and autoimmunity.

Mast cells (MCs) are major effector cells in allergic diseases. Recently, it has become evident that the contribution of MCs extends far beyond their accepted role in allergic disease, and that they play a more extensive role in a variety of non-allergic immune processes such as the innate immunity response. These cells have a key role in both the induction and elicitation of several autoimmune conditions. Targeting MC development, maturation or activation may be of value in future prevention and treatment of autoimmune conditions.

Autoimmunity↗
PubMed2004

Chlamydia pneumoniae and future risk in patients with coronary heart disease.

AIM: To evaluate the association between previous exposure to Chlamydia pneumoniae and future coronary risk in patients with coronary heart disease. METHODS: A prospective, nested, case-control design was used. The patient sample was derived from a trial study of bezafibrate for the treatment of coronary heart disease. Anti-Chlamydia pneumoniae antibodies (IgG and IgA) in the baseline sera of 136 patients who had coronary events during follow-up (mean 6.2 years) were compared with those in 136 age- and gender-matched patients from the same trial without subsequent coronary events. RESULTS: Mean titers of IgG and IgA antibodies were similar in cases and controls. The relative odds of future coronary events in patients who were seropositive at baseline were 1.0 (95% CI, 0.54-1.84) for IgG and 0.74 (95% CI, 0.41-1.31) for IgA. The relative odds did not change after adjustment for multiple confounding variables. The risk of future coronary events did not increase with increasing anti-Chlamydia pneumoniae antibody titers. CONCLUSIONS: Prior exposure to Chlamydia pneumoniae in patients with chronic coronary heart disease is not associated with increased risk of recurrent coronary events.

Antibodies, Bacterial↗
PubMed2003

Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis.

Mastocytosis is a rare disease characterized by accumulation of mast cells in tissues. To investigate whether an altered regulation of mast cell apoptosis might be involved in the pathogenesis of mastocytosis, expression of the apoptosis-preventing molecules bcl-2 and bcl-xL was studied by immunohistochemistry in skin and bone marrow lesions of mastocytosis patients. In addition, reverse transcription-polymerase chain reaction was used to investigate levels of bcl-2 and bcl-xL mRNA in cutaneous mastocytosis lesions. Since activating mutations of c-kit are known to be associated with some forms of mastocytosis, human mast cell cultures were also stimulated via c-kit and the expression of bcl-2 and bcl-xL was assessed by immunoblotting. In patients with mastocytosis, the expression of bcl-2 protein but not bcl-xL in cutaneous mast cells was significantly enhanced, compared to healthy controls. Evaluating different subgroups of adult and pediatric mastocytosis patients, all groups were found to express significantly increased levels of bcl-2 protein, and none of the patient groups was found to overexpress bcl-xL, with the exception of solitary mastocytomas that showed a tendency for up-regulated bcl-xL protein. Furthermore, the expression of bcl-2 mRNA was significantly enhanced in cutaneous lesions of adult and pediatric patients, while bcl-xL mRNA levels were only slightly increased in pediatric, but not in adult patients with mastocytosis. In contrast to the skin lesions, bone marrow infiltrates of patients with systemic mastocytosis showed only low or absent immunoreactivity for bcl-2, but marked expression of bcl-xL. In vitro, stimulation of two different mast cell culture systems by activation of c-kit resulted in up-regulation of bcl-2 and also in an increase of bcl-xL, although less pronounced. Thus, overexpression of bcl-2 and bcl-xL leading to prolonged survival of mast cells may contribute to the pathogenesis of mastocytosis. Our findings may help to develop new strategies for the treatment of this disease.

Adult↗
PubMed2003

Prospective study of Chlamydia pneumoniae IgG and IgA seropositivity and risk of incident ischemic stroke.

BACKGROUND AND PURPOSE: Chlamydia pneumoniae infection or exposure to C. pneumoniae was implicated as a risk factor for ischemic stroke. Our aim was to evaluate prospectively the association between the presence of antibodies to C. pneumoniae (IgG and IgA) and the risk of incident ischemic stroke among patients with pre-existing vascular disease. METHODS: Sera were collected from 3,090 coronary heart disease patients enrolled in a secondary prevention trial. We measured baseline antibodies (IgG and IgA) in the sera of patients who developed subsequent ischemic strokes (cases, n = 134) during follow-up (mean 8.2 years), and in 134 age- and gender-matched pairs without subsequent stroke or myocardial infarction. RESULTS: The crude relative odds (95%CI) of incident ischemic strokes in seropositive patients at baseline (>1.1 relative value units) were 1.29 (95%CI, 0.69-2.47) for IgG and 1.31 (95% CI, 0.69-2.55) for IgA by matched-pair analyses, and 1.42 (95%CI, 0.69-2.98) for IgG and 1.57 (95%CI, 0.76-3.35) for IgA after adjustments for conventional risk factors and the inflammatory marker, soluble intercellular adhesion molecule-1. We explored the possibility that the risk of ischemic stroke may increase in parallel to increasing antibody titers, but did not demonstrate any significant association. CONCLUSIONS: Serological evidence for prior infection with C. pneumoniae did not emerge as an independent risk factor for incident ischemic stroke among patients at high risk due to pre-existing vascular disease.

Aged↗
PubMed2002

Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease. Data from the Bezafibrate Infarction Prevention (BIP) Study.

OBJECTIVES: The goal of this study was to assess soluble intercellular adhesion molecule-1 (sICAM-1) level as a predictor of future acute coronary events in patients with chronic coronary heart disease (CHD). BACKGROUND: Increased sICAM-1 concentration has been shown to be associated with the incidence of CHD in healthy persons. Its significance in patients with CHD has been scarcely investigated. METHODS: We designed a prospective, nested case-control study. Sera were collected from patients with CHD enrolled in a secondary prevention trial that evaluated the efficacy of bezafibrate in reducing coronary events. We measured baseline sICAM-1 concentration in the sera of patients who developed subsequent cardiovascular events (cases: n = 136) during follow-up (mean: 6.2 years) and in age- and gender-matched controls (without events: n = 136). RESULTS: Baseline serum concentrations of sICAM-1 were significantly higher in cases versus controls (375 vs. 350 ng/ml; p < 0.05). Each 100 ng/ml increase in sICAM-1 concentration was associated with 1.27 (95% confidence interval [CI]: 1.00 to 1.63) higher relative odds of coronary events. Soluble ICAM-1 concentration in the highest quartile (>394 ng/ml) was associated with significantly higher odds of coronary events (compared with the lowest quartile), even after multivariate adjustment (2.31, 95% CI: 1.02 to 5.50). After adding fibrinogen and total white blood cell count to the multivariate model, the relative odds were 2.12 (95% CI: 0.88 to 5.35) and 2.70 (95% CI: 1.10 to 7.05), respectively. CONCLUSIONS: Elevated sICAM-1 concentration in CHD patients is associated with increased risk of future coronary events independent of other traditional risk factors.

Bezafibrate↗
PubMed2002

Synaptotagmin II negatively regulates MHC class II presentation by mast cells.

Synaptotagmins (Syts), comprise a gene family of proteins, implicated in the control of protein traffic. Rat basophilic leukemia cells (RBL-2H3), a tumor analogue of mucosal mast cells (MMC), express at least four distinct Syt homologues, including Syt II, Syt III, Syt V and Syt IX. Synaptotagmin II is located at the late/endosomal/lysosomal compartment, where it negatively regulates lysosomal exocytosis. Mast cells may contribute to immune defense mechanisms by presenting MHC class II/antigen complexes and triggering T cell-dependent immune responses. We now demonstrate that RBL-2H3 mast cells, which express reduced levels of Syt II (<5%) by transfection with Syt II antisense cDNA, are able to release MHC class II molecules. We further show that release of both MHC class II molecules and of the lysosomal enzyme cathepsin D is stimulated by lipopolysaccharide (LPS, 1 microg/ml, 48h). We show further that LPS reduces by >40% the level of Syt II expression in both RBL-2H3 and bone marrow-derived mast cells (BMMC). This effect is both dose and time-dependent. These results indicate that Syt II can be down-regulated by external inflammatory signals, resulting in the amplification of mast cell function. Finally, our results implicate Syt II as an important and novel regulator of MHC class II presentation.

Animals↗
PubMed2002

Heterotypic adhesion-induced mast cell activation: biologic relevance in the inflammatory context.

In addition to being a major effector cell in the elicitation of allergic inflammation, mast cells have been found to be activated in various T cell-mediated inflammatory processes and to reside in close physical proximity to T cells. Such observations have led investigators to propose a functional relationship between these two cell populations. In this regard, we have recently reported that murine and human mast cells can be activated to both release granule-associated mediators, such as histamine and matrix metalloproteinase-9 (MMP-9), and to produce several cytokines (i.e. TNF-alpha, IL-4 and IL-6) upon physical contact, which is adhesion molecule mediated, with activated T cells. This cascade of events, whereby mast cells are activated by T cells to release certain mediators which are known to be essential for leukocyte extravasation and recruitment to affected sites, points to an important immunoregulatory function of mast cells within the context of T cell-mediated inflammatory processes.

Autocrine Communication↗
PubMed2002

Soluble intercellular adhesion molecule-1 and risk of future ischemic stroke: a nested case-control study from the Bezafibrate Infarction Prevention (BIP) study cohort.

BACKGROUND AND PURPOSE: Inflammation is considered to be involved in the pathogenesis of ischemic stroke. Our purpose was to assess the role of soluble intercellular adhesion molecule-1 (sICAM-1) concentration, a marker of inflammation, in predicting future ischemic stroke among patients at risk because of chronic coronary heart disease. METHODS: We obtained baseline serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention trial (n=3090), which assessed the efficacy of bezafibrate in secondary prevention. Using a prospective nested case-control design, we measured baseline sICAM-1 concentration in sera of patients who developed ischemic stroke during a mean follow-up of 8.2 years (cases, n=134) and in age- and sex-matched controls without any subsequent cardiovascular events (n=134). RESULTS: Baseline serum concentrations of sICAM-1 were significantly higher in cases compared with controls (379 versus 350 ng/mL, P<0.05). sICAM-1 concentration at the highest quartile (>394 ng/mL) was associated with significantly higher relative odds of ischemic stroke compared with the lower concentrations after adjustment for potential confounding variables (relative odds, 2.1; 95% CI, 1.1 to 4.3). After fibrinogen and total white blood cell count were added to the multivariable model, the relative odds were 2.1 (95% CI, 1.1 to 4.2) and 2.2 (95% CI, 1.1 to 4.8), respectively. The risk associated with raised concentrations of sICAM-1 seemed to be highest for large disabling strokes of cardioembolic origin. CONCLUSIONS: Elevated concentrations of sICAM-1, a marker of inflammation, are associated with increased risk of ischemic stroke, independent of other traditional cerebrovascular risk factors and of plasma fibrinogen, among patients at increased risk because of manifest coronary heart disease.

Bezafibrate↗