Biomedical subjects

Ana Tobar

Publications and source records attributed to Ana Tobar.

10 recordsLinked to original sources

PubMed2004

Administration of eptifibatide to acute coronary syndrome patients receiving enoxaparin or unfractionated heparin: effect on platelet function and thrombus formation.

OBJECTIVES: The goal of this study was to compare the antithrombotic effects of enoxaparin versus unfractionated heparin (UFH) when combined with eptifibatide in acute coronary syndrome (ACS) patients. BACKGROUND: An increasing number of high-risk ACS patients are treated with low-molecular-weight heparin and a glycoprotein (GP) IIb/IIIa inhibitor. There is a paucity of data regarding the antithrombotic properties of such a combination as compared with UFH and GP IIb/IIIa inhibitors. METHODS: Twenty-six ACS patients scheduled to undergo coronary angiography were treated with subcutaneous enoxaparin (n = 13) or intravenous UFH (n = 13). All patients received eptifibatide just before coronary angiography. Antithrombotic effects were assessed as changes in platelet-thrombus formation using the Badimon ex vivo perfusion chamber. Perfusions were carried out at a high shear rate (HSR) and a low shear rate (LSR). Patients underwent two perfusion studies: at baseline (under enoxaparin or UFH) and 10 min after the eptifibatide bolus. Platelet function was evaluated by ADP-induced platelet aggregation and the rapid platelet function analyzer. RESULTS: Both therapeutic combinations achieved a marked reduction in platelet aggregation after eptifibatide (83% to 89.7% reduction in the enoxaparin-eptifibatide group and 77.8% to 85.5% reduction in the UFH-eptifibatide group, inter-group differences not significant). Both groups also demonstrated marked reductions in thrombus formation, but the reductions achieved in the enoxaparin-eptifibatide group were significantly higher than those achieved in the UFH-eptifibatide group (HSR: 75.6% reduction vs. 63.9%, respectively, p = 0.01; LSR: 79.7% reduction vs. 66.1%, respectively, p = 0.0001). CONCLUSIONS: The combination of eptifibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptifibatide and UFH in the doses tested.

Anticoagulants↗

PubMed2004

Inhibition of interleukin-10 by the immunomodulator AS101 reduces mesangial cell proliferation in experimental mesangioproliferative glomerulonephritis: association with dephosphorylation of STAT3.

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease. Using an acute model of mesangial proliferative glomerulonephritis (Thy1 GN), we show that neutralization of interleukin (IL)-10 greatly ameliorated the disease as expressed by both decreased MC expansion and proteinuria. Treatment with the tellurium compound AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) resulted in favorable effects provided that the compound was administered 24 h before insult, whereas partial effects were obtained when administered after insult. We identified STAT3 as playing a pivotal role in IL-10-induced MC proliferation in vitro and in vivo. IL-10 activates MC STAT3 in vitro as expressed by its phosphorylation and nuclear translocation. The role of STAT3 in MC proliferation induced by IL-10 was deduced from results showing that IL-10-induced proliferation was abrogated if MC transfected with STAT3 antisense oligonucleotides were used or if cells were incubated with inhibitors of STAT3. AS101 deactivates STAT3 in control but not in MC transfected with IL-10 antisense oligonucleotides. Inactivation of STAT3 prevents reduction of MC proliferation by AS101. We further demonstrate the role of STAT3 in the regulation of cell cycle and survival regulatory proteins by AS101 in MC via inhibition of IL-10. IL-10 increased MC expression of Bcl-2 and Bcl-X1 and simultaneously decreased the levels of p27kip1. These survival factors were decreased by AS101 in a STAT3- and IL-10-dependent manner, whereas p27kip1 was similarly increased. In Thy1 GN, phosphorylated STAT3 in glomerular MC peaked at day 6 and correlated with MC expansion. Neutralization of IL-10 or its inhibition by AS101 abolished phosphorylation of STAT3. This effect positively correlated with amelioration of the disease. These in vitro and in vivo studies indicate that the autocrine MC growth factor IL-10 induces MC proliferation via STAT3. We suggest that IL-10 or its downstream target STAT3 might be therapeutic targets for kidney diseases induced by mesangial proliferation.

Active Transport, Cell Nucleus↗

PubMed2004

Familial thymic cyst.

Thymic cysts are rare lesions of the anterior mediastinum or neck. The majority are asymptomatic, and the remainder are associated mainly with symptoms of dysphagia or dyspnea. Diagnosis is difficult before surgery. Cervical thymic cysts are relatively rare; age at presentation ranges from the neonatal period to adulthood, and the most frequent presenting sign is a lateral neck mass. Mediastinal thymic cysts are more common and account for 1% of all mediastinal masses. They tend to occur in the older age group and are usually detected incidentally on chest X-ray film or computed tomography scans. Dysphagia and dyspnea are the main symptoms. We describe two brothers, aged 5 and 8 years, with mediastinal thymic cysts that presented as low cervical masses and review the embryology, diagnosis and management of thymic cysts.

Child↗

PubMed2004

A case of Langerhans'-cell histiocytosis with membranous nephropathy.

A 26-year-old man with a history of Langerhans'-cell histiocytosis (LCH) of the bone presented with nephrotic-range proteinuria. Renal biopsy results showed changes characteristic of membranous nephropathy. During the current hospitalization, the patient had 2 episodes of pulmonary embolism. LCH at this time was documented in the lymph nodes. The patient was treated with repeated courses of vinblastine and high doses of corticosteroids to achieve remission of the basic disease and the renal involvement. After 2 years, complete remission of both the lymphadenopathy and the nephrotic syndrome was achieved. The association of membranous nephropathy with LCH might be attributable to an underlying abnormality in the immune system, a paraneoplastic manifestation, or both. This is the first report of LCH associated with severe nephrotic syndrome caused by membranous nephropathy.

Adult↗

PubMed2003

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Antibodies, Antineutrophil Cytoplasmic↗

PubMed2003

Does vascular endothelial growth factor (VEGF) play a role in the pathogenesis of minimal change disease?

BACKGROUND: Minimal change disease (MCD) is one of the major causes of nephrotic syndrome both in children and adults. The pathogenesis of this condition is not clear and it has been suggested that a plasma permeability factor may play a role. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been thought to be one the factors involved. The aim of this study was thus to investigate the role of VEGF in the pathogenesis of MCD. METHODS: The expression of the gene for VEGF and VEGF receptor-2 (VEGFR-2) was estimated using in situ hybridization in renal biopsy specimens taken from patients with nephrotic syndrome and diagnosed histologically as MCD. The results were compared with those obtained in normal renal tissue. Biopsy specimens from eight patients diagnosed as having MCD were randomly selected for the study. The patients were aged 4-60 years at the time of the biopsy. There were four females and four males. All patients had presented with a nephrotic syndrome, five with recent onset of the disease, two with repeated attacks of the syndrome and one had reduced renal function. RESULTS: The gene expression for VEGF, measured as the proportional glomerular area occupied by autoradiographic grains, was significantly less in the patients with MCD than in controls (1.9 +/- 0.4 vs 4.8 +/- 0.6%, P < 0.0025), whereas the gene expression for VEGFR-2 was no different to controls (1.9 +/- 0.4 vs 2.0 +/- 0.2%). CONCLUSIONS: MCD is associated with a reduction in the expression of the gene for VEGF. As VEGF may play an important role in renal repair and survival, it is postulated that the deficiency, which we have shown, may lead to the dysregulation of the repair process in MCD.

Adult↗

PubMed2003

Production of the novel mesangial autocrine growth factors GDNF and IL-10 is regulated by the immunomodulator AS101.

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.

Adjuvants, Immunologic↗

PubMed2002

Relationship of tumorigenic malignant melanomas to dermal elastin: an expression of tumor/stromal interaction that may be related to prognosis.

Malignant melanomas, which produce a large number of substances active in connective tissue modulation, must contend with the dermis to grow and propagate. We studied the morphologic interactions between tumorigenic malignant melanomas and dermal elastin. Formalin-fixed and paraffin-embedded tissues of 108 tumorigenic malignant melanomas were stained for elastic tissue with the Verhoeff-van Gieson method. Various aspects of the relationship between malignant melanoma and dermal elastin were analyzed in relation to the histologic and clinical data using univariate and multivariate analyses. Tumor thickness, mitotic rate, and the presence of elastin remnants within the tumors were found to be independent negative prognostic factors, the latter with borderline significance. Tumors with more remnants of elastin were associated with higher stage of disease and lymph node and distant metastases. Tumor infiltration between the elastic fibers in the tumor depth was associated with high Clark level, greater tumor thickness, high stage of disease, and lymph node metastases. At least partial preservation of elastic fibers in the tumor depth was a relatively good prognostic factor whereas complete absence of elastin was an adverse factor. Focal or multifocal absence of elastin in the midst of the tumors or in their depth was usually associated with lymphocytic infiltrates. We suggest that tumors with remnants of elastic fibers and/or invasion between elastic fibers in their depth may be fast growing and highly invasive. The absence of elastin within tumors and at their advancing edge may be related to the elaboration of elastin-degrading substances by melanoma cells or various inflammatory cells. Our findings indicate that the relationship between malignant melanomas and dermal connective tissue components, specifically elastin, may have prognostic significance.

Adolescent↗

PubMed2002

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

Animals↗

PubMed2002

Using the automated biopsy gun with real-time ultrasound for native renal biopsy.

BACKGROUND: The use of an automated biopsy system for renal biopsy has recently gained popularity, but its safety in single functioning kidneys is unclear. OBJECTIVE: To report our experience with the automated system for closed renal biopsy during a 5 year period. METHODS: Eighty-five patients underwent percutaneous native renal biopsy with the automated biopsy gun (16G needle) under real-time ultrasound. They were chronologically divided into two groups: 41 patients (group A), using an older ultrasound machine; and 44 patients (group B), using a newer ultrasound machine. Nine patients biopsied with a manual 14G Tru-cut needle served as the control (group C). RESULTS: The number of "attempted" passes at the kidney was 4.0 +/- 0.1 in group B, 4.7 +/- 0.3 in group A (P < 0.05 vs. group B), and 5.8 +/- 0.5 in group C (P < 0.01 vs. group B). The number of successful passes did not differ (3.3 +/- 0.1, 3.3 +/- 0.1, 3.1 +/- 0.2). The ratio of "attempted/successful" was 1.28 +/- 0.07 in group B, 1.95 +/- 0.38 in A, and 1.90 +/- 0.21 in C (P < 0.01 vs. B). The number of glomeruli obtained was similar in the three groups. Adequate tissue was obtained in 95%, 98%, and 100%, respectively. Hemoglobin decreased by 4.3 +/- 1.1% in group B, 6.9 +/- 1.3% in group A, and 11.3 +/- 1.8% in group C (P < 0.05 vs. B). Perinephric/subcapsular hematoma occurred in 5 patients (11.4%) in group A (2 taking aspirin), in 2 patients (4.9%) in group B, and in none in group C. The necessity for blood transfusion post-biopsy was similar in all groups. Four of five patients with single functioning kidneys (one in group A and four in group B) had uneventful biopsies, and adequate tissue was obtained in three. CONCLUSIONS: The use of the automated biopsy gun is effective, safe and has a low rate of major complications. It may be used safely in single functioning kidneys.

Adolescent↗