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Biomedical subjects

Pablo Ortiz

Publications and source records attributed to Pablo Ortiz.

12 recordsLinked to original sources
PubMed2006

Clinical trial of a leucotriene B4 receptor antagonist, BIIL 284, in patients with rheumatoid arthritis.

BACKGROUND: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA. METHODS: This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months' duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20. RESULTS: Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated. CONCLUSIONS: This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.

Administration, Oral↗
PubMed2004

Finite elements using a plane-wave basis for scattering of surface water waves.

A generalized, frequency-independent, finite-element method is proposed for the numerical simulation of combined diffraction, refraction, radiation, reflection and absorption of water waves. Plane waves are used as an external function space, exploiting the standard set of approximation functions defined by the finite element method to enforce conformity and to impose boundary conditions in a straightforward manner by applying the method to the plane waves on each element. An integration method originally devised only for diffraction of waves by Ortiz and Sanchez in 2001 is extended to combined refraction and diffraction of high-frequency waves, retaining its dramatic savings in the number of operations for a given error compared with standard numerical integration methods.

Journal Article↗
PubMed2004

Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study.

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Clinical and histological variables that predict survival, such as Breslow's index, tumor size, ulceration, or vascular invasion have been identified in malignant melanoma. Nevertheless, the potential relevance of biological variables still awaits an in-depth exploration. Using tissue microarrays (TMAs), we retrospectively analyzed 165 malignant melanoma samples from 88 patients corresponding to distinct histological progression phases, radial, vertical, and metastases. A panel of 39 different antibodies for cell cycle, apoptosis, melanoma antigens, transcription factors, DNA mismatch repair, and other proteins was used. Integrating the information, the study has identified expression profiles distinguishing specific melanoma progression stages. Most of the detected alterations were linked to the control of cell cycle G1/S transition; cyclin D1 was expressed in radial cases 48% (12 of 25) with significant lost of expression in vertical cases 14% (9 of 65), P = 0.002; whereas p16(INK4a) (89% in vertical versus 71% in metastatic cases, P = 0.009) and p27(KIP1) (76% in radial versus 45% in vertical cases, P = 0.010) were diminished in advanced stages. The study also defines a combination of biological markers associated with shorter overall survival in patients with vertical growth phase melanoma, that provided a predictor model with four antibodies (Ki67, p16(INK4a), p21(CIP1), and Bcl-6). This predictor model was validated using an independent series of 72 vertical growth phase melanoma patients.

Adult↗
PubMed2004

Transcriptional response of T cells to IFN-alpha: changes induced in IFN-alpha-sensitive and resistant cutaneous T cell lymphoma.

Interferon-alpha (IFN-alpha) therapy is commonly used in the treatment of neoplastic and autoimmune diseases, including cutaneous T cell lymphoma (CTCL). However, the IFN-alpha response is unpredictable, and the IFN-alpha cell targets and pathways are only partially understood. To delineate the molecular mechanisms of IFN-alpha activity, gene expression profiling was performed in a time-course experiment of both IFN-alpha sensitive and IFN-alpha-resistant variants of a CTCL cell line. These experiments revealed that IFN-alpha is responsible for the regulation of hundreds of genes in both variants and predominantly involves genes implicated in signal transduction, cell cycle control, apoptosis, and transcription regulation. Specifically, the IFN-alpha response of tumoral T cells is due to a combination of induction of apoptosis in which TNFSF10 and HSXIAPAF1 may play an important role and cell cycle arrest achieved by downregulation of CDK4 and CCNG2 and upregulation of CDKN2C and tumor suppressor genes (TSGs). Resistance to IFN-alpha appears to be associated with failure to induce IRF1 and IRF7 and deregulation of the apoptotic signals of HSXIAPAF1, TRADD, BAD, and BNIP3. Additionally, cell cycle progression is heralded by upregulation of CDC25A and CDC42. A critical role of NF-kappaB in promoting cell survival in IFN-alpha-resistant cells is indicated by the upregulation of RELB and LTB.

Cell Line, Tumor↗
PubMed2003

Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study.

Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma, whose diagnosis and study is hampered by its morphologic similarity to inflammatory dermatoses (ID) and the low proportion of tumoral cells, which often account for only 5% to 10% of the total tissue cells. cDNA microarray studies using the CNIO OncoChip of 29 MF and 11 ID cases revealed a signature of 27 genes implicated in the tumorigenesis of MF, including tumor necrosis factor receptor (TNFR)-dependent apoptosis regulators, STAT4, CD40L, and other oncogenes and apoptosis inhibitors. Subsequently a 6-gene prediction model was constructed that is capable of distinguishing MF and ID cases with unprecedented accuracy. This model correctly predicted the class of 97% of cases in a blind test validation using 24 MF patients with low clinical stages. Unsupervised hierarchic clustering has revealed 2 major subclasses of MF, one of which tends to include more aggressive-type MF cases including tumoral MF forms. Furthermore, signatures associated with abnormal immunophenotype (11 genes) and tumor stage disease (5 genes) were identified.

Cluster Analysis↗
PubMed2002

High-salt diet increases sensitivity to NO and eNOS expression but not NO production in THALs.

L-Arginine inhibits thick ascending limb (THAL) NaCl absorption by activating endothelial NO synthase (eNOS) and increasing NO production. Inhibition of renal NO production combined with a high-salt diet produces hypertension, and the THAL has been implicated in salt-sensitive hypertension. We hypothesized that a high-salt diet enhances the inhibitory action of L-arginine on NaCl absorption by THALs because of increased eNOS expression and NO production. To test this, we used isolated THALs from rats on a normal-salt (NS) or high-salt diet (HS) for 7 to 10 days. L-Arginine (1 mmol/L) decreased chloride absorption by 56+/-10% in THALs from rats on a HS diet, but only 29+/-3% in THALs from rats on a NS diet. eNOS expression in isolated THALs from rats on a HS diet was increased by 3.9-fold compared with NS (P<0.03). However, L-arginine increased NO levels to the same extent in THALs from both groups, as measured with DAF-2 DA or a NO-sensitive electrode. To determine whether a HS diet increases the sensitivity of the THAL to NO, we tested the effects of the NO donor spermine NONOate on chloride absorption. In THALs from rats on a HS diet, 1 and 5 micromol/L spermine NONOate reduced chloride absorption by 35+/-5% and 58+/-6%, respectively. In contrast, these same concentrations of spermine NONOate reduced chloride absorption by 4+/-4% (P<0.03 versus HS diet) and 43+/-9% in THALs from rats on a NS diet. We conclude that a HS diet enhances the effect of NO in the THAL. L-Arginine-stimulated NO production was not enhanced by a HS diet, despite increased eNOS protein.

Animals↗
PubMed2002

S-adenosyl-L-methionine prevents 5-HT(1A) receptors up-regulation induced by acute imipramine in the frontal cortex of the rat.

S-adenosyl-L-methionine (SAM) has shown efficacy in speeding the onset of the antidepressant effect of imipramine in depressed patients. This effect may be related to their interactions at the serotonin(1A) (5-HT(1A)) receptors. Acute imipramine up-regulated the frontal cortex 5-HT(1A) receptors (B(max), 51.5 +/- 8.4 fmol/mg protein) vs. saline (B(max), 27.5 +/- 5.9 fmol/mg protein), and did not show antidepressant effect. Acute SAM and imipramine+SAM did not modify frontal cortex 5-HT(1A) receptors, and showed antidepressant effects (decrease of the immobility response of 26%, P<0.01; and 47%, P<0.001) vs. saline. All the chronic treatments showed antidepressant effects and up-regulated the hippocampus 5-HT(1A) receptors. SAM prevents the 5-HT(1A) receptor up-regulation induced by acute imipramine in the frontal cortex. This mechanism may contribute to imipramine's antidepressant effect.

Animals↗
PubMed2002

Molecular epidemiology of molluscum contagiosum virus and analysis of the host-serum antibody response in Spanish HIV-negative patients.

Molluscum contagiosum virus (MCV) lesions from Spanish human immunodeficiency virus (HIV)-negative patients were clinically examined and analyzed for virus detection and typing. In a study of 147 patients, 97 (66%) were children under 10 years, of whom 49% had atopic dermatitis. MCV lesions were morphologically indistinguishable among the different age groups, but atopic patients presented larger lesions compared with patients without the disorder. In adults, lesions were observed mainly on the genitals. MCVI was the predominant subtype. The deduced MCVI/MCVII ratio (146:1) was much higher than that found in other geographical areas. Protein preparations of the virus-induced lesions were immunoblotted with sera from 25 MCVI patients. The host-serum antibody response was weak and variable, although no significant differences were found between atopic and nonatopic patients. Three immunoreactive proteins of 74/80, 60, and 35 kDa were detected in almost all the analyzed sera. The 35 and 74/80-kDa proteins were virus specific, whereas the 60-kDa protein band was composed of a mix of human keratins. Immunoblotting of MCV lesions and vaccinia virus-infected cell extracts with either MCV patient serum or a rabbit antiserum against vaccinia virus showed no cross-reactivity of these two human poxviruses at the antigenic level.

Adolescent↗
PubMed2002

Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma.

Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.

Antineoplastic Agents↗
PubMed2002

Effects of dipyrone on inflammatory infiltration and oxidative metabolism in gastric mucosa: comparison with acetaminophen and diclofenac.

In the last several years, it has been proposed that neutrophil- and oxygen-dependent microvascular injuries may be important factors in the gastrointestinal toxicity of nonsteroidal antiinflammatory drugs (NSAIDs). In addition, after oral administration, reduced levels of gastric mucosal adenosine triphosphate in response to mitochondrial damage constitute the earliest event on topical mucosal erosions. In these experiments, we compared the implication of active oxygen, lipid peroxidation levels and neutrophil infiltration in gastric mucosal injury induced by the analgesic-antipyretic drugs, dipyrone (pyrazolone derivative) and acetaminophen (nonacidic drug), both with relatively weak antiinflammatory effects, with diclofenac (an acidic NSAID). After 6 hr of oral administration, dipyrone (120 and 500 mg/kg) did not provoke macroscopic lesions on rat gastric mucosa. Only the highest dose (1000 mg/kg) induced slight erosions similar to the same dose of acetaminophen without modifications in lipid peroxidation levels or myeloperoxidase activity. The area of mucosa with lesions, the increase in neutrophil infiltration, and concentration of TBA-reactive substances was significantly higher with diclofenac (50 mg/kg). By contrast, inhibition in superoxide dismutase activity was observed. In a dose-dependent manner, dipyrone and diclofenac decreased the levels of endogenous gluthatione, and the highest dose (1000 mg/kg) also inhibited glutathione peroxidase activity. None of treatments induced changes in xanthine oxidase activity, an index of ischemic condition. These findings confirm the favorable gastric tolerability of dipyrone, since only the highest dose produced weak mucosal lesions similar to that obtained with acetaminophen, and this effect only could be related to a diminished glutathione metabolism. In contrast, diclofenac induced significant erosions, and the data obtained indicate that the enhancement of oxidative stress plays an important role in the pathogenesis of damage.

Acetaminophen↗
PubMed2002

Gastrointestinal tolerability of metamizol, acetaminophen, and diclofenac in subchronic treatment in rats.

The gastrointestinal tolerability of metamizol and acetaminophen [weak cyclooxygenase (COX) inhibitors] in comparison with diclofenac (nonselective cyclooxygenase inhibitor) was evaluated in subchronic treatments in rats. Wistar rats received 60 mg/kg body weight of metamizol and acetaminophen, and 3 mg/kg body weight of diclofenac by oral route twice daily for 14 days. Myeloperoxidase activity, an index of neutrophil infiltration, COX expression and the effects on blood parameters used as indicators of liver and renal functions were also studied. Metamizol and acetaminophen did not cause apparent gastrointestinal lesions; in contrast diclofenac showed swelling and an increased thickness on the distal intestinal mucosa. Myeloperoxidase activity was significantly increased in the small bowel with diclofenac treatment. In gastric mucosa the expression of the cyclooxygenase-1 was not affected and the expression of cyclooxygenase-2 was not observed. Diclofenac treatment significantly diminished hematocrit, hemoglobin, and corpuscular volume and increased the number of platelets. Aspartate aminotransferase and gamma-glutamyltransferase activity were also altered and, regarding the renal biochemical parameters, the animals treated with diclofenac had increased urea values. In contrast, acetaminophen treatment did not affect either of these parameters and metamizol increased only the alanine aminotransferase activity. Under our experimental conditions, metamizol and acetaminophen seem to be safe drugs. In contrast, with diclofenac treatment blood loss and anemia are observed which could stem from the small intestinal injury. Moreover, this drug could to impair kidney function.

Acetaminophen↗